Liver Toxicity Induced by Combined External-Beam Irradiation and Radioimmunoglobulin Therapy

Abstract

High-dose radiation therapy for liver metastases of gastrointestinal malignancies might be improved by combining external-beam irradiation and radioimmunoglobulin therapy. We studied the liver toxicity of the proposed combination in healthy beagle dogs. A total dose of 30 Gy to the whole liver, delivered in 2-Gy fractions over 3 weeks, resulted in mild, temporary veno-occlusive disease (VOD) in three of three dogs. Reversible bone marrow damage was noted after two intravenous injections of 18.5 MBq of yttrium-90-labeled monoclonal antibody ZCE025 per kg body weight in three of three dogs. Administrations of the antibody were 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 dogs were euthanized in a stage of terminal liver failure around day 90 after treatment. Temporary bone marrow damage was observed after the combined treatment, similar to the bone marrow damage observed after radioimmunoglobulin therapy alone. Earlier studies in the same dog model showed that bone marrow is the dose-limiting organ if radioimmunoglobulin 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 similar to that observed in humans and is reflected in early platelet consumption in the irradiated liver plus late elevations of liver enzymes and VOD in central hepatic veins on histological analysis. Future applications of combined liver irradiation and radioimmunoglobulin therapy in humans should use radioimmunoglobulin therapy agents which show minimal uptake by normal liver.

x-Irradiation in Rat Liver: Consequent Upregulation of Hepcidin and Downregulation of Hemojuvelin and Ferroportin-1 Gene Expression

“…The threshold dose for wholeliver irradiation without chemotherapy is supposed to be 20 -30 Gy (21,22). In patients who undergo combined radiation therapy and chemotherapy or combined radiation therapy and immunotherapy, the risk for development of radiation-induced liver disease is higher (23,24). Findings in studies in animals have suggested that liver irradiation at a dose higher than the threshold dose is followed by progressive liver fibrosis and cirrhosis (25).…”

Irradiation leads to sensitization of hepatocytes to TNF-α-mediated apoptosis by upregulation of IκB expression

“…On the other hand, the liver is a highly radiosensitive organ: the development of radiation-induced liver disease (RILD) is considered to be a major dose limiting complication in abdominal irradiation [8]. The threshold dose for whole liver irradiation is assumed to be between 20 and 30 Gy [9].…”

Radioimmunotherapy of Colorectal Cancer Liver Metastases: Combination with Radiotherapy

“…An experimental study of combined RT and RIT has been performed in beagle dogs. In the combined therapy group, two of three dogs had to be sacrificed because of liver radiation necrosis and 30% weight loss 4. The liver toxicity might have been partially due to the use of 90 Y‐labeled MAbs that resulted in a nonspecific accumulation in the liver.…”