Hepatotoxicity Associated with CCNU (Lomustine) Chemotherapy in Dogs

Abstract

One hundred seventy-nine tumor-bearing dogs were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) between 1995 and 2001. CCNU was given as a single dose of 50-110 mg/m2 body surface area PO. Treatment interval varied, but the minimal interval between CCNU doses was 3 weeks. After treatment, 11 dogs (6.1%) developed hepatic toxicity. The median number of CCNU doses and the median total cumulative CCNU dose were significantly higher in dogs that developed hepatic toxicity (4 doses; 350 mg/m2) than in dogs without hepatic damage (3 doses; 230 mg/m2). Median duration to detection of hepatic toxicity from the last dose of CCNU was 11 weeks (range 2-49 weeks). Common biochemical abnormalities were abnormally high serum liver enzyme activities and hypoalbuminemia. Six dogs with CCNU-associated hepatic toxicity had ascites, and 3 dogs had concurrent pleural effusion. Serum concentrations of bile acids were abnormally high in 4 of 5 dogs tested. Percutaneous ultrasound-guided liver biopsies were performed in 10 dogs, and findings were nonspecific and chronic in nature. Seven dogs were euthanized because of progressive liver failure, and their median survival from diagnosis of liver disease was 9 weeks. Three dogs died of other causes and 1 dog of unknown cause. Although clinical signs resolved in 3 dogs, biochemical abnormalities and histopathologic lesions persisted 4 to 38 months from the time of diagnosis of liver disease. Our findings suggest that CCNU can cause delayed, cumulative dose-related, chronic hepatotoxicity that is irreversible and can be fatal.

Combination Chemotherapy with Continuous l‐Asparaginase, Lomustine, and Prednisone for Relapsed Canine Lymphoma

“…Hepatotoxicity associated with lomustine chemotherapy was reported in a previous study by Kristal et al 23 Although none of the dogs in the present study developed definitive evidence of overt liver failure, there was a significant trend toward increasing mean ALT activity over time. Lomustine dose reductions were necessary in 3 dogs, and discontinuation was required in 2.…”

Combination of CCNU and DTIC Chemotherapy for Treatment of Resistant Lymphoma in Dogs

“…In the present study, the CCNU‐DTIC protocol was discontinued based on increases in ALT activity alone; only 3 of the 7 dogs had evidence of liver dysfunction (based on hyperbilirubinemia in 1 dog and increased postprandial bile acid concentrations in 2 dogs). Because definitions varied, direct comparisons between the incidence of liver toxicity in the study reported here and the frequency in the report by Kristal et al 30 cannot be made. However, the median number of CCNU doses and median total cumulative CCNU dose in dogs with suspected hepatic damage were lower than the values reported by Kristal et al 30 (2 doses, 80 mg/m 2 versus 4 doses, 350 mg/m 2 ).…”

“…Because definitions varied, direct comparisons between the incidence of liver toxicity in the study reported here and the frequency in the report by Kristal et al 30 cannot be made. However, the median number of CCNU doses and median total cumulative CCNU dose in dogs with suspected hepatic damage were lower than the values reported by Kristal et al 30 (2 doses, 80 mg/m 2 versus 4 doses, 350 mg/m 2 ). This observation might suggest an additive or synergistic toxicity when CCNU and DTIC are combined.…”

“…In a large retrospective study, hepatotoxicity was documented in 11 of 179 (6%) dogs treated with CCNU. Criteria for hepatotoxicity in that study included clinical, serum biochemical, and histopathological changes identified after CCNU therapy 30 . In the present study, the CCNU‐DTIC protocol was discontinued based on increases in ALT activity alone; only 3 of the 7 dogs had evidence of liver dysfunction (based on hyperbilirubinemia in 1 dog and increased postprandial bile acid concentrations in 2 dogs).…”

ACVIM consensus statement on the diagnosis and treatment of chronic hepatitis in dogs

“…Most often they cause acute injury, but in some instances CH or cirrhosis are potential sequele. Strong evidence indicates that treatment with phenobarbital, primidone, phenytoin, and lomustine can result in CH . In the case of phenobarbital, toxicity may be direct or related to altered metabolism of other xenobiotics.…”