Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients.
OBJECTIVE
The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide.


METHODS
Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function.


RESULTS
An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals.


CONCLUSIONS
Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.
Gomez
J L
JL
Department of Medicine, Centre Hospitalier de l'Université Laval Research Center, Quebec, Canada.
Dupont
A
A
Cusan
L
L
Tremblay
M
M
Suburu
R
R
Lemay
M
M
Labrie
F
F
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase / Q000097:blood; D000726:Androgen Antagonists / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D005485:Flutamide / Q000008:administration & dosage / Q000009:adverse effects*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D015994:Incidence; D008107:Liver Diseases / Q000201:enzymology / Q000453:epidemiology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D012306:Risk; D005723:gamma-Glutamyltransferase / Q000097:blood
D000726:Androgen Antagonists; C062225:LHRH, Trp(6)-des-GlyNH2(10)-; D007987:Gonadotropin-Releasing Hormone; D005485:Flutamide; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D001663:Bilirubin