|Reviewer: Ryan Smith, MD|
Authors: M Kojima, K Kamoi, O Ukimura, et al.
Flutamide, an antiandrogen, is used to treat patients with prostate cancer. As the indications for adjuvant androgen ablation in prostate cancer grow, the use of flutamide will become more widespread. However, its use has been associated with hepatopathy, likely due to binding of cytochrome P-450 and the inhibition of mitochondrial ATP synthesis. The incidence of this toxicity has been estimated to be 10-20%. Ursodeoxycholic acid (UDCA) is a cholic acid that has been used to treat drug-induced hepatopathy, recently shown in animal models to treat and even prevent flutamide-induced hepatotoxicity. This study is a retrospective report on the validity of the use of UDCA in the prevention of flutamide-induced hepatopathy.
The use of flutamide and other antiandrogen agents is increasing in the treatment of prostate cancer. Hepatopathy is a common toxicity and cause for concern when prescribing these drugs. This study attempts to demonstrate the efficacy of UDCA in the prevention of this flutamide-induced hepatotoxicity. From this data, the rate of hepatopathy decreased from 32.4% to 11.4% with the addition of UDCA to flutamide. A couple of points should be mentioned. First, a hepatopathy rate of 32.4% is very high when compared to historical data. This is likely due to the strict definition of hepatopathy used in this paper. There is a question as to whether patients with Grade 1 toxicity, as defined by this report, is actually clinically significant. In fact, many clinicians would not discontinue flutamide until the increase in the liver enzymes were >2.5 fold above the upper limit of normal, which would be a Grade 2 toxicity in this paper. The vast majority of the hepatopathies and hepatopathies prevented with UDCA were Grade 1. Therefore, although the number of hepatopathies were decreased, whether this is clinically significant can be debated. However, there were no Grade 3 or 4 toxicities in the UDCA group compared to 3 patients with Grade 3 and 4 hepatotoxicity in the flutamide alone group. Though the numbers are small, if these toxicities could be prevented, it would have a definite clinical impact.
The results of this study are encouraging, though to fully test the efficacy of UDCA in the prevention of flutamide induced hepatopathy, a prospective and randomized study needs to be done, with attention on the prevention of clinically significant hepatotoxicity.