LIVER TOXICITY INDUCED BY COMBINED EXTERNAL-BEAM IRRADIATION AND RADIOIMMUNOGLOBULIN THERAPY

High-dose radiation therapy for liver metastases of gastrointestinal m alignancies might be improved by combining external-beam irradiation a nd radioimmunoglobulin therapy, We studied the liver toxicity of the p roposed combination in healthy beagle dogs. A total dose of 30 Gy to t he whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. R eversible bone marrow damage was noted after two intravenous injection s of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody we re separated by 1 week. Three dogs treated by irradiation of the liver with radioimmunoglobulin therapy added during the last 2 weeks of the irradiation showed signs of radiation hepatitis (VOD) starting around 35 days after treatment. One dog had a complete recovery, and two dog s were euthanized in a stage of terminal liver failure around day 90 a fter treatment. Temporary bone marrow damage was observed after the co mbined treatment, similar to the bone marrow damage observed after rad ioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobu lin therapy is used alone. The addition of irradiation of the liver to radioimmunoglobulin therapy changes the dose-limiting organ from bone marrow to liver. The radiation hepatitis observed in dogs is very sim ilar to that observed in humans and is reflected in early platelet con sumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future app lications of combined liver irradiation and radioimmunoglobulin therap y in humans should use radioimmunoglobulin therapy agents which show m inimal uptake by normal liver. (C) 1995 by Radiation Research Society