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Fulminant hepatic failure associated with bicalutamide
FULMINANT LAURA
HEPATIC FAILURE ASSOCIATED WITH BICALUTAMIDE
A. DAWSON,
EDWARD
CHOW,
AND
GERARD
MORTON
ABSTRACT
Bicalutamide is a new, nonsteroidal antiandrogen with a favorable toxicity profile. We report the first case of fulminant hepatic failure associated with its use. Copyright 1997 by Ekevier Science Inc. UROLOGY 49: 283-284, i 997.
A
60-year-old man with no prior history of liver disease received androgen blockade and localized radiation therapy for a T3c, Nl, MO, Gleason grade 7 adenocarcinoma of the prostate. Following an initial month of cytoproterone acetate 100 mg three times daily, total androgen blockade consisting of flutamide 250 mg three times daily and monthly subcutaneous goserelin acetate 3.6 mg was commenced. Although flutamide was well tolerated with no apparent ill effects, it was discontinued after 3 months and bicalutamide (Casodex; Zeneca Pharmaceuticals, Wilmington, Del) 50 mg daily was introduced in its place. After the second dose of bicalutamide, the patient developed confusion, jaundice, and encephalopathy. There was no history of travel, blood transfusions, tattoos, intravenous (IV) drug use, recent alcohol intake, or acetaminophen use. The following laboratory values were abnormal: bilirubin, 333 pmol/L (normal less than 20); aspartate aminotransferase, 1527 III/L (normal less than 31); alanine aminotransferase, 2690 IU/L (normal less than 31), alkaline phosphatase, 181 IU/L (normal 40 to 120); gamma-glutamyl transpeptidase, 121 IU/L (normal less than 50); lactate dehydrogenase, 535 IU/L (normal 100 to 250); prothrombin time (International Normalized Ratio), 2.21 (normal 0.81 to 1.2); partial thromboplastin time, 40.1 seconds (normal 26 to 35); platelet count 107 X 109/L (normal 150 to 400 X 109). Hepatitis A, B, and C screening and the monospot test were
From the Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, Toronto, Ontario, Canada Reprint requests: Gerard Morton, M.D., Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Baview Avenue, North York, Ontario, M4N 31115, Canada Submitted: July 2, 1996, accepted: August 7, 1996 COPYRIGHT
1997
ALL
RESERVED
RIGHTS
BY ELSEVIER
SCIENCE
INC.
negative. An acetaminophen blood level was zero. An abdominal ultrasound revealed no evidence of cholestatic obstruction or liver metastasis. Liver enzymes had been tested 1 year prior to bicalutamide administration and were normal. Bicalutamide became the suspected cause of the acute hepatic encephalopathy, and it was discontinued. With supportive IV fluids, vitamin K, and lactulose, the hepatic failure improved. Within 2 months, the prothrombin time, bilirubin, and liver enzymes normalized. An unexplained thrombocytopenia subsequently developed. Folate levels, vitamin Blz levels, and a bone marrow biopsy were normal, consistent with idiopathic thrombocytopenia. Platelets remained less than 30 X lo9 for at least 3 months. COMMENT Androgen ablation remains the standard treatment for patients with metastatic prostate cancer. Recently, it has been shown to be of benefit in the neoadjuvant setting. Bicalutamide is a recently introduced nonsteroidal antiandrogen with the advantage of once-daily administration and less reported toxicity compared with flutamide and nilutamide.lm3 No casesof bicalutamide-associated hepatic failure have been reported in the literature, whereas fatal hepatic failure has been reported in patients treated with flutamide and nilutamide.4-6 In a trial comparing bicalutamide plus a leutinizing hormone-releasing hormone analogue (LHRH-A) to flutamide plus an LHRH-A, elevation of liver enzymes occurred in 25 of 401 (6%) patients treated with bicalutamide versus 40 of 407 (10%) patients treated with flutamide. Jaundice was reported with a similar incidence for bicalutamide and flutamide, 6 of 401 (1.5%) and 8 of 407 (2.0%), respectively.’ 0090-4295/97/$17.00 PI1 SOO90-4295(96)00355-X
283
The hepatic failure in our case was attributed to bicalutamide because of the absence of other etiologic factors, the temporal relation with bicalutamide administration, laboratory evaluations, and the resolution of the hepatitis following bicalutamide discontinuation. It is possible that the previous administration of cytoproterone and flutamide may have sensitized the patient to bicalutamide. Alternatively, subclinical hepatic damage may have developed prior to bicalutamide administration, inducing a slow metabolism and toxic buildup of bicalutamide. Possible mechanisms of bicalutamide-induced hepatotoxicity include an idiosyncratic reaction, direct hepatotoxicity, and cholestatic hepatitis. Idiosyncratic, immunologically mediated hepatotoxicity is unpredictable and infrequent, with no dose-response relationship. In contrast, direct hepatotoxicity occurs predictably with dose-dependence. Finally, bicalutamide causes an increase in testosterone, which may impair liver function via cholestatic hepatitis. We speculate that bicalutamide induced an idiosyncratic hepatotoxicity reaction in our patient. Although bicalutamide has been shown to be better tolerated than other antiandrogens, it is not without risk of serious hepatic complications. Our patient developed potentially fatal hepatotoxicity while on bicalutamide. This supports the need for monitoring liver enzymes prior to and routinely during bicalutamide therapy because early liver
284
damage is reversible and progression to liver failure can be prevented. Bicalutamide should be discontinued should clinical hepatitis or elevation of liver enzymes develop. It should also be used cautiously in patients with any history of liver abnormalities. REFERENCES 1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, and Kolvenbag G, for the Casodex Combination Study Group: A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology 45: 745-752, 1995. 2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, and Kolvenbag G: Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Urology 47 (suppl IA): 54-60, 80-84, 1996. 3. Kolvenbag GJ, and Blackledge GR: Worldwide activity and safety of bicalutamide: a summary review. Urology 47 (suppl IA): 70-84, 1996. 4. Wysowski DK, Freiman JP, Tourtelot JB, Horton ML III, and Horton ML: Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 118: 860-864, 1993. 5. Hart W, and Stricker BH: Flutamide and hepatitis. Ann Intern Med 110: 860-864, 1989. 6. Pescatore P, Hammel P, Durand F, Bertheau P, Bernuau J, Hut D, Gerbal JL, Degott C, and Benhamou JP: Hepatite fulminante mortelle imputable au nilutamide (Anandron) [Fatal fulminant hepatitis induced by nilutamide (Anandron)]. Gastroenterol Clin Biol 17: 499-501, 1993.
UROLOGY
49 (2), 1997
HEPATIC FAILURE ASSOCIATED WITH BICALUTAMIDE
A. DAWSON,
EDWARD
CHOW,
AND
GERARD
MORTON
ABSTRACT
Bicalutamide is a new, nonsteroidal antiandrogen with a favorable toxicity profile. We report the first case of fulminant hepatic failure associated with its use. Copyright 1997 by Ekevier Science Inc. UROLOGY 49: 283-284, i 997.
A
60-year-old man with no prior history of liver disease received androgen blockade and localized radiation therapy for a T3c, Nl, MO, Gleason grade 7 adenocarcinoma of the prostate. Following an initial month of cytoproterone acetate 100 mg three times daily, total androgen blockade consisting of flutamide 250 mg three times daily and monthly subcutaneous goserelin acetate 3.6 mg was commenced. Although flutamide was well tolerated with no apparent ill effects, it was discontinued after 3 months and bicalutamide (Casodex; Zeneca Pharmaceuticals, Wilmington, Del) 50 mg daily was introduced in its place. After the second dose of bicalutamide, the patient developed confusion, jaundice, and encephalopathy. There was no history of travel, blood transfusions, tattoos, intravenous (IV) drug use, recent alcohol intake, or acetaminophen use. The following laboratory values were abnormal: bilirubin, 333 pmol/L (normal less than 20); aspartate aminotransferase, 1527 III/L (normal less than 31); alanine aminotransferase, 2690 IU/L (normal less than 31), alkaline phosphatase, 181 IU/L (normal 40 to 120); gamma-glutamyl transpeptidase, 121 IU/L (normal less than 50); lactate dehydrogenase, 535 IU/L (normal 100 to 250); prothrombin time (International Normalized Ratio), 2.21 (normal 0.81 to 1.2); partial thromboplastin time, 40.1 seconds (normal 26 to 35); platelet count 107 X 109/L (normal 150 to 400 X 109). Hepatitis A, B, and C screening and the monospot test were
From the Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, University of Toronto, Toronto, Ontario, Canada Reprint requests: Gerard Morton, M.D., Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Baview Avenue, North York, Ontario, M4N 31115, Canada Submitted: July 2, 1996, accepted: August 7, 1996 COPYRIGHT
1997
ALL
RESERVED
RIGHTS
BY ELSEVIER
SCIENCE
INC.
negative. An acetaminophen blood level was zero. An abdominal ultrasound revealed no evidence of cholestatic obstruction or liver metastasis. Liver enzymes had been tested 1 year prior to bicalutamide administration and were normal. Bicalutamide became the suspected cause of the acute hepatic encephalopathy, and it was discontinued. With supportive IV fluids, vitamin K, and lactulose, the hepatic failure improved. Within 2 months, the prothrombin time, bilirubin, and liver enzymes normalized. An unexplained thrombocytopenia subsequently developed. Folate levels, vitamin Blz levels, and a bone marrow biopsy were normal, consistent with idiopathic thrombocytopenia. Platelets remained less than 30 X lo9 for at least 3 months. COMMENT Androgen ablation remains the standard treatment for patients with metastatic prostate cancer. Recently, it has been shown to be of benefit in the neoadjuvant setting. Bicalutamide is a recently introduced nonsteroidal antiandrogen with the advantage of once-daily administration and less reported toxicity compared with flutamide and nilutamide.lm3 No casesof bicalutamide-associated hepatic failure have been reported in the literature, whereas fatal hepatic failure has been reported in patients treated with flutamide and nilutamide.4-6 In a trial comparing bicalutamide plus a leutinizing hormone-releasing hormone analogue (LHRH-A) to flutamide plus an LHRH-A, elevation of liver enzymes occurred in 25 of 401 (6%) patients treated with bicalutamide versus 40 of 407 (10%) patients treated with flutamide. Jaundice was reported with a similar incidence for bicalutamide and flutamide, 6 of 401 (1.5%) and 8 of 407 (2.0%), respectively.’ 0090-4295/97/$17.00 PI1 SOO90-4295(96)00355-X
283
The hepatic failure in our case was attributed to bicalutamide because of the absence of other etiologic factors, the temporal relation with bicalutamide administration, laboratory evaluations, and the resolution of the hepatitis following bicalutamide discontinuation. It is possible that the previous administration of cytoproterone and flutamide may have sensitized the patient to bicalutamide. Alternatively, subclinical hepatic damage may have developed prior to bicalutamide administration, inducing a slow metabolism and toxic buildup of bicalutamide. Possible mechanisms of bicalutamide-induced hepatotoxicity include an idiosyncratic reaction, direct hepatotoxicity, and cholestatic hepatitis. Idiosyncratic, immunologically mediated hepatotoxicity is unpredictable and infrequent, with no dose-response relationship. In contrast, direct hepatotoxicity occurs predictably with dose-dependence. Finally, bicalutamide causes an increase in testosterone, which may impair liver function via cholestatic hepatitis. We speculate that bicalutamide induced an idiosyncratic hepatotoxicity reaction in our patient. Although bicalutamide has been shown to be better tolerated than other antiandrogens, it is not without risk of serious hepatic complications. Our patient developed potentially fatal hepatotoxicity while on bicalutamide. This supports the need for monitoring liver enzymes prior to and routinely during bicalutamide therapy because early liver
284
damage is reversible and progression to liver failure can be prevented. Bicalutamide should be discontinued should clinical hepatitis or elevation of liver enzymes develop. It should also be used cautiously in patients with any history of liver abnormalities. REFERENCES 1. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, and Kolvenbag G, for the Casodex Combination Study Group: A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Urology 45: 745-752, 1995. 2. Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, and Kolvenbag G: Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Urology 47 (suppl IA): 54-60, 80-84, 1996. 3. Kolvenbag GJ, and Blackledge GR: Worldwide activity and safety of bicalutamide: a summary review. Urology 47 (suppl IA): 70-84, 1996. 4. Wysowski DK, Freiman JP, Tourtelot JB, Horton ML III, and Horton ML: Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 118: 860-864, 1993. 5. Hart W, and Stricker BH: Flutamide and hepatitis. Ann Intern Med 110: 860-864, 1989. 6. Pescatore P, Hammel P, Durand F, Bertheau P, Bernuau J, Hut D, Gerbal JL, Degott C, and Benhamou JP: Hepatite fulminante mortelle imputable au nilutamide (Anandron) [Fatal fulminant hepatitis induced by nilutamide (Anandron)]. Gastroenterol Clin Biol 17: 499-501, 1993.
UROLOGY
49 (2), 1997