Radioimmunotherapy of small volume disease of colorectal cancer metastaticto 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 freq uent 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 colo n 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 thera peutic efficacy of RAIT in colorectal cancer patients with small volume dis ease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were in duced by intrasplenic injection of a 10% tumor cell suspension. Whereas con trols were left untreated, therapy was initiated on day 10 or 20 after tumo r inoculation with the I-131-labeled, low affinity anticarcinoembryonic ant igen (anti-CEA) monoclonal antibody (MAb), F023C5 (K-a = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (K-a = 10(9) liters/mol), or chem otherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at th eir respective maximum tolerated doses (MTDs). Twelve colorectal cancer pat ients with small volume disease metastatic to the liver (all lesions less t han or equal to 2.5 cm) were entered into a mCi/m(2)-based Phase I dose esc alation study with I-131-labeled humanized version of MN-14, hMN 14. The pa tients were given single injections, starting at 50 mCi/m(2) and escalating in 10-mCi/m(2) increments. The MTD was defined as the dose level at which less than or equal to 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metas tases at 6-8 weeks after tumor inoculation. The life span of mice treated w ith 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas iri notecan led to a 5-8-week prolongation, In contrast, at their respective MT Ds, the I-131-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% perma nent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent c ure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, I-131-F023C5 was u nable to achieve cures, whereas I-131-MN-14 was still successful in 20%. Hi stologically, no remaining viable tumor cells could be demonstrated in thes e animals surviving >6 months. In patients, the MTD was reached at 60 mCi/m(2) of hMN-14 (at 70 mCi/m(2), two of three grade 4 myelotoxicities). Of 11 assessable patients, 2 had par tial 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 co nventional chemotherapy. Antibodies of higher affinity seem to be clearly s uperior. The clinical response rates in patients with small volume disease are encouraging, being comparable to the response rates of conventional che motherapeutic regimens but with fewer side effects. Ongoing studies will sh ow whether treatment at the MTD will further improve therapeutic results.