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 i s below 30%, despite the development and use of a variety of chemotherapeut ic regimens. Therefore, new therapeutic strategies are warranted. Whereas r adioimmunotherapy (RIT) has shown disappointing results in bulky disease, i t may be a promising therapeutic alternative in limited and small volume di sease. The aim of this study was, therefore, to compare, in a preclinical s tudy, the therapeutic efficacy of RIT in colorectal cancer to equitoxic che motherapy, as well as to evaluate, in a pilot clinical trial, its efficacy in small volume disease. Nude mice, bearing subcutaneous or metastatic huma n colon cancer xenografts, were injected either with the unlabeled (131)lab eled monoclonal antibodies (MAbs), (CO17-1A or (which is a murine IgG(2a) d irected against a 41-kD membrane glycoprotein) or F023C5 (which is an anti- CEA MAb of murine IgG(1) subtype), or were administered 5-fluorouracil / fo linic acid (5-FU/LV) at equitoxic doses. In a pilot clinical study, 10 colo rectal cancer patients with small volume metastatic disease tall lesions le ss than or equal to 3 cm) have been entered so far in an ongoing mCi/m(2)-b ased dose escalation study with the I-131-labeled F023C5. In the animals, t he maximum tolerated activities (MTD) of I-131-labeled CO17-1A and F023C5 w ere 300 mu Ci and 600 mu Ci, respectively corresponding to blood doses of a pproximately 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 intrave nous bolus I h apart for 5 subsequent clays. Whereas no significant therape utic effects were seen with both unlabeled MAbs or 5-FU/LV chemotherapy, tu mor growth was retarded significantly with both radiolabeled antibodies. li t the metastatic model, chemotherapy prolonged life for only a few weeks, w hereas RIT led to cures in 35-55% of the animals. As was the case in the an imals, myelotoxicity seems to be dose-limiting in patients as well. Encoura ging anti-tumor effects were observed lasting for up to more than 12 months . These data suggest that radioimmunotherapy may be a viable therapeutic op tion in colorectal cancer patients with limited disease. Myelotoxicity is t he only dose-limiting organ toxicity. Although most patients were treated b elow the MTD, anti-tumor effects are encouraging. Further studies are ongoi ng.