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/m 2 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/m 2 ) than in dogs without hepatic damage (3 doses; 230 mg/m 2 ). 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 L-asparaginase, Lomustine, and Prednisone for Relapsed or Refractory Canine Lymphoma

“…Liver biopsies performed in 10 of the dogs demonstrated nonspecific, chronic findings. 13 Although none of the dogs in the present study developed definitive evidence of overt liver failure, several dogs had increases in ALT while receiving lomustine, and a statistically significant increase in ALT was documented in cases where pre-and post-treatment values were available. When rechecked, these values had normalized after discontinuation of the protocol, but no biopsies were performed to document cause or duration of liver changes.…”

“…In humans, this drug has been used most commonly for treatment of brain tumors and LSA. 9 Reported toxicities include cumulative myelosuppression (leukopenia with delayed thrombocytopenia) [9][10][11][12] ; liver toxicity 13 ; and, rarely, renal failure. 9,12 Lomustine has been previously studied as a rescue agent for canine LSA, under the premise that refractory LSA is less likely to reveal cross-resistance to alkylating agents, thus they may be more effective in re-inducing a clinical remission, even in drug resistant patients.…”

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…In the patient with PHS elevation of serum activities of enzymes ALT and SAP, which are biomarkers of liver function, was observed. However, this change occurred a week after induction of chemotherapy with CCNU, which exhibits known hepatotoxicity (Kristal et al, 2004). In the first two weeks after EGT, before the chemotherapy was started, no abnormalities in bloodwork were observed in this patient, despite detecting elevated serum levels of IFN-γ in blood samples collected 7 and 14 days after EGT.…”

Clinical and laboratorial evaluation of dogs with cutaneous lymphoma treated with lomustine

“…On the other hand, the toxicological potential of this drug has been evaluated and its use has been associated with side effects. Myelosuppression is the most frequent side effect, followed by gastrointestinal signs (KRISTAL et al, 2004;HEADING et al, 2011).…”