Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver: preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study.

At the time of surgery, occult metastases (micrometastases) are present in more than 50% of colorectal cancer patients, and the liver is the most frequent site of apparent metastatic disease. Frequently, adjuvant chemotherapy is unable to prevent tumor recurrence. Thus, novel therapeutic strategies are warranted. The aim of this study was to establish a model of human colon cancer metastatic to the liver of nude mice, to assess, in this setting, the therapeutic efficacy of radioimmunotherapy (RAIT) compared to standard chemotherapy and to evaluate, in a Phase I/II trial, the toxicity and therapeutic efficacy of RAIT in colorectal cancer patients with small volume disease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were induced by intrasplenic injection of a 10% tumor cell suspension. Whereas controls were left untreated, therapy was initiated on day 10 or 20 after tumor inoculation with the 131I-labeled, low affinity anticarcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb), F023C5 (Ka = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (Ka = 10(9) liters/mol), or chemotherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at their respective maximum tolerated doses (MTDs). Twelve colorectal cancer patients with small volume disease metastatic to the liver (all lesions < or = 2.5 cm) were entered into a mCi/m2-based Phase I dose escalation study with 131I-labeled humanized version of MN-14, hMN-14. The patients were given single injections, starting at 50 mCi/m2 and escalating in 10-mCi/m2 increments. The MTD was defined as the dose level at which < or = 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation. The life span of mice treated with 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas irinotecan led to a 5-8-week prolongation. In contrast, at their respective MTDs, the 131I-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% permanent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent cure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, 131I-F023C5 was unable to achieve cures, whereas 131I-MN-14 was still successful in 20%. Histologically, no remaining viable tumor cells could be demonstrated in these animals surviving > 6 months. In patients, the MTD was reached at 60 mCi/m2 of hMN-14 (at 70 mCi/m2, two of three grade 4 myelotoxicities). Of 11 assessable patients, 2 had partial remissions (corresponding to an objective response rate of 18%), and 5 (45%) had minor/mixed responses or experienced stabilization of previously rapidly progressing disease. These data suggest that in small volume disease, RAIT may be superior to conventional chemotherapy. Antibodies of higher affinity seem to be clearly superior. The clinical response rates in patients with small volume disease are encouraging, being comparable to the response rates of conventional chemotherapeutic regimens but with fewer side effects. Ongoing studies will show whether treatment at the MTD will further improve therapeutic results.

Radioimmunotherapy of colorectal cancer in small volume disease and in an adjuvant setting: preclinical evaluation in comparison to equitoxic chemotherapy and initial results of an ongoing phase-I/II clinical trial.

The 5-year survival of colorectal cancer patients with distant metastases is below 30%, despite the development and use of a variety of chemotherapeutic regimens. Therefore, new therapeutic strategies are warranted. Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky disease, it may be a promising therapeutic alternative in limited and small volume disease. The aim of this study was, therefore, to compare, in a preclinical study, the therapeutic efficacy of RIT in colorectal cancer to equitoxic chemotherapy, as well as to evaluate, in a pilot clinical trial, its efficacy in small volume disease. Nude mice, bearing subcutaneous or metastatic human colon cancer xenografts, were injected either with the unlabeled or 131I-labeled monoclonal antibodies (MAbs), CO17-1A (which is a murine IgG2a directed against a 41-kD membrane glycoprotein) or F023C5 (which is an anti-CEA MAb of murine IgG1 subtype), or were administered 5-fluorouracil/folinic acid (5-FU/LV) at equitoxic doses. In a pilot clinical study, 10 colorectal cancer patients with small volume metastatic disease (all lesions < or = 3 cm) have been entered so far in an ongoing mCi/m2-based dose escalation study with the 131I-labeled F023C5. In the animals, the maximum tolerated activities (MTD) of 131I-labeled CO17-1A and F023C5 were 300 microCi and 600 microCi, respectively, corresponding to blood doses of approximately 15 Gy each. Accordingly, myelotoxicity was dose-limiting. The MTD in the chemotherapy group was 0.6 mg 5-FU/1.8 mg LV, given as intravenous bolus 1 h apart for 5 subsequent days. Whereas no significant therapeutic effects were seen with both unlabeled MAbs or 5-FU/LV chemotherapy, tumor growth was retarded significantly with both radiolabeled antibodies. In the metastatic model, chemotherapy prolonged life for only a few weeks, whereas RIT led to cures in 35-55% of the animals. As was the case in the animals, myelotoxicity seems to be dose-limiting in patients as well. Encouraging anti-tumor effects were observed, lasting for up to more than 12 months. These data suggest that radioimmunotherapy may be a viable therapeutic option in colorectal cancer patients with limited disease. Myelotoxicity is the only dose-limiting organ toxicity. Although most patients were treated below the MTD, anti-tumor effects are encouraging. Further studies are ongoing.

[Somatostatin receptor scintigraphy in neuroendocrine tumors exemplified by a patient with hepatic metastases of gastrinoma]. / Somatostatin-Rezeptor-Szintigraphie bei neuroendokrinen Tumoren am Beispiel einer Patientin mit hepatisch metastasiertem Gastrinom.

In a 66-year old woman, who suffered from recurrent melena, diarrhea and hematemesis with multiple untreatable gastric and duodenal ulcers, a markedly increased basal and secretin-stimulated gastrin level, clinically a Zollinger-Ellison syndrome was assumed. The conventional diagnostic procedures (esophago-gastro-duodenoscopy, colonoscopy, endosonography, ERCP, abdominal CT and small bowel enema) had failed to reveal the localisation of any gastrinoma. The thereupon performed scintigraphy with In-111-pentetreotide showed four somatostatin receptor expressing liver lesions: two of them could be detected at first site in the consecutively performed MR scans, another retrospectively bearing in mind the scintigraphic images. Today, the somatostatin receptor imaging seems to be a highly sensitive procedure for detecting and localizing hormonally active gastroenteropancreatic tumors. At the same time it is a method for in vivo evaluation of the somatostatin receptor status of localized GEP tumors, thus delivering a decisive diagnostic step for the evaluation of the effectiveness of a therapy with somatostatin analogues before such an expensive therapy is started.