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.
Behr
T M
TM
Department of Nuclear Medicine, Georg-August-University of Göttingen, Germany.
Memtsoudis
S
S
Vougioukas
V
V
Liersch
T
T
Gratz
S
S
Schmidt
F
F
Lorf
T
T
Post
S
S
Wörmann
B
B
Hiddemann
W
W
Ringe
B
B
Becker
W
W
D000818:Animals; D000911:Antibodies, Monoclonal; D000931:Antidotes / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D002955:Leucovorin / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D010865:Pilot Projects; D016499:Radioimmunotherapy / Q000009:adverse effects; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002272:Carcinoembryonic Antigen; D007457:Iodine Radioisotopes; D002955:Leucovorin; D005472:Fluorouracil