Liver disease as an adverse event for men on ADT


A newly published article in the Journal of Urology has indicated risk of an association between treatment with androgen deprivation therapy (ADT) and risk for a spectrum of liver disorders.

The new paper by Gild et al. is based on an analysis of data from just under 83,000 men aged 66 and older accumulated in the SEER (Surveillance, Epidemiology and End Results)-Medicare database from 1992 to 2009. All these patients were initially diagnosed with localized prostate cancer.

Gild et al. excluded from their analysis any men who, at the time of their diagnosis with prostate cancer, were known to have a preexisting form of nonalcoholic fatty liver disease (NAFLD), other liver disease, diabetes, or metabolic syndrome.

They were able to show the following:

  • 37.5 percent of the eligible patients were treated with ADT; they were studied in three groups.
    • Men who had up to seven monthly equivalent doses of an LHRH agonist or antagonist
    • Men who had between seven and 11 monthly equivalent doses of an LHRH agonist or antagonist
    • Men who > 11 monthly equivalent doses of an LHRH agonist or antagonist
  • Overall, compared to men who receive no ADT, these men were more likely to be diagnosed with
    • NAFLD (hazard ratio [HR] = 1.54)
    • Cirrhosis of the liver (HR = 1.35)
    • Liver necrosis (HR = 1.41)
    • Liver disease of any type (HR = 1.47)
  • There was a dose-response relationship between the number of ADT doses and the occurrence of NAFLD and liver disease of any type.

The authors conclude that ADT in men with prostate cancer is

… associated with the diagnosis of nonalcoholic fatty liver disease. The usual limitations of an observational study design apply, including possible inaccuracy in defining outcomes in a population based registry.

In editorial comments on this paper, Pinthus notes that NAFLD is the most common cause of liver disease in Western counties, but goes on to point out that:

This is an important observation because it highlights a clinically important metabolic perturbation of ADT which is probably unfamiliar to most urologists.

He goes on to note that

  • NAFLD is in and of itself a spectrum of liver disorders.
  • Diagnosis of NAFLD is challenging.
  • The mechanism by which ADT induces the onset of NAFLD is unknown.

However, what seems to be clear is that this is one more set of potentially long-term risks associated with ADT in the treatment of prostate cancer.

This is a potential consequence of treatment with ADT that all prostate cancer support group leaders and other educators should now add to the list of known adverse events associated with ADT.

4 Responses

  1. Long-known Association of Antiandrogen Therapy and Impact on the Liver, But Likely Less Known to Urologists

    As a veteran of more than 14 years of intermittent ADT (starting in December 1999 and including Lupron and mostly bicalutamide, with bicalutamide started around March of 2000, but also flutamide for my last cycle of ADT before hopefully curative radiation in 2013), being in the on-therapy cycle somewhat less than half of that time, I was well aware of the risk of liver damage, potentially serious and life-threatening, posed by antiandrogen therapy, and I was also aware of the highly effective standard countermeasures that should be employed.

    My recollection is that the official prescribing directions for antiandrogens require liver function tests until it is established that the patient’s biology is not subject to liver damage from antiandrogen therapy. That is typically established quickly, with just a few months of liver function tests. The vast majority of patients will not have a liver problem with antiandrogen therapy; for the rest, the liver function tests provide timely warning to cease the therapy before there is substantial damage. Moreover, certain medical countermeasures, such as the drug ursodiol, can be used to enable some men to safely continue antiandrogen therapy who would otherwise suffer liver damage. This risk of liver damage due to antiandrogens has been known for many years and has been very well studied. For example, searching PubMed (www.pubmed.gov) with the search string “liver AND prostate cancer AND (antiandrogen OR Casodex OR flutamide)”, with filters activated for Abstract, Humans, Male, Field: Title/Abstract, yielded 67 hits this morning, with 57 of those hits more than 10 years old. That said, my impression is that urologists are far less aware of this risk and the countermeasures needed than are oncologists. (After all, surgeons are accustomed to bringing a knife to a drug fight. LOL.)

    What I suspect is that much of the increase in risk of about 33% to 50% over the baseline risk (prevalence of about 30-40% in the US; see here) is due to use of antiandrogens without proper countermeasures. However, I also expect that some is due to the combination of likelihoods that ADT for locally advanced patients is much more likely to be associated with more advanced cases, and that those more advanced cases are more likely to be a proxy for unfavorable diet and other lifestyle choices which are going to raise the risk of NAFLD regardless of ADT. I doubt that the authors tried to filter out this artifactual influence, a task which was probably daunting because of the limitations of the SEER data set but might have been attempted by pulling in other research. It is also reasonable that ADT had some adverse impact beyond these influences, but I suspect that separate impact is likely rather small. Also, there are countermeasures available for ADT side effects, including the specific effects of NAFLD, for which there is substantial evidence of effectiveness, such as exercise, good diet and nutrition choices, and the drug metformin.

    Despite these criticisms, this paper will probably bring needed attention to these threats in the urology community, as the authors themselves have pointed out, and that is definitely of value.

  2. Does any of the leadership in the USA medical oncology community/doctors acknowledge this? It seems that, if these findings can be reproduced by other studies, this is as big a red flag on ADT as we have see yet.

    Maybe we can narrow down which drugs and dosages over time have the highest chance to induce liver disease.

    Mike Brown

  3. Dear Mike:

    Since this paper is the first to ever report such a finding, and it was just published in September, I am not sure what you mean by the question, “Does any of the leadership in the USA medical oncology community/doctors acknowledge this?” It will take time to confirm a finding like this. I have seen no signal that anyone is denying it, and it is likely that the FDA and other regulatory authorities are looking at these data to see if this side effect should be added to others listed in the prescribing information for — at the least — the LHRH agonists.

    As you point out, it will be important to see if the same outcome can be reproduced in at least one other comparable set of data before anyone starts leaping to conclusions.

    With regard to whether it would be possible to “narrow down which drugs and dosages … have the highest chance to induce liver disease”, that would probably be extremely difficult. And there are other associated issues that would come into play. The association that has been postulated may not simply be a side effect of a set of drugs (let alone just some of these drugs).

  4. Hi Mike, please see my first response! This is well understood, the ways to manage and counter the risk are well understood, and this knowledge has been available for around three decades! Try this PubMed search: antiandrogen AND liver AND prostate cancer , with filters (on the left of the screen) for Abstract, Humans, and Title/Abstract (under Search Fields following Show Additional Filters). That search, as of this morning, yielded 40 papers (you can read the abstracts if you click on the blue hypertext). The oldest regarding liver damage was from 1992!

    Moreover, while I haven’t checked, I am highly confident that the liver risk issue and management tactics are prominent in the prescribing information for antiandrogens. By antiandrogens I mean flutamide, Casodex/bicalutamide, nilutamide, and perhaps the new generation antiandrogens: Xtandi/enzalutamide and Erleada/apalutamide. (Cyproterone acetate is not available in the US.) Off the top of my head I believe I read that one or both of the latter drugs have a reduced or no risk of liver damage, but that recollection is hazy.

    As for the need for new studies, it would be interesting to see a study of patients who had received antiandrogens but who had not had liver function tests. That study would be particularly interesting to malpractice attorneys!

    My strong impression is that no risk of liver disease is associated with the LHRH-agonist or LHRH-antagonist drugs (not counting combined use with antiandrogens).

    I am a nineteen year survivor of once life-threatening prostate cancer, and antiandrogen drugs were a pillar of may intermittent androgen deprivation strategy for the first fourteen years (had radiation in 2013 and stopped ADT in 2014). I had liver function tests for the first few months I was on Casodex, which determined that I would not suffer liver damage from the drug.

    Sometimes in medicine the left hand doesn’t know what the right hand is doing!

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