Sixty-five-year-old George Lincoln* never suspected that anything was wrong. Aside from some of the typical side effects of hormone therapy for his prostate cancer, such as fatigue, occasional hot flashes, mild weight gain, and a loss of libido, he felt okay. He didn’t have abdominal pain, nausea, jaundice, or any other symptoms that might indicate a potentially life-threatening problem.
|*Editor’s note: To protect his privacy, the patient’s name has been changed. All medical details are as reported. In keeping with editorial policy, the patient’s physicians are not named. Our Editor in Chief, Marc B. Garnick, M.D., narrates Lincoln’s story. He also shares his advice on avoiding a serious, though relatively uncommon, side effect of anti-androgens.|
But after Lincoln had a blood test to check his liver function on Sept. 21, 2006, his doctor told him to immediately stop taking bicalutamide (Casodex), the anti-androgen he had been taking with a drug called leuprolide (Lupron) for just a month. Test results indicated that levels of certain liver enzymes had skyrocketed beyond normal levels, raising the possibility of hepatitis, liver damage, liver failure, and even death.
Lincoln was lucky. After he stopped taking the anti-androgen, his elevated liver enzymes slowly dropped. Five months later, they were back to normal levels, and he shows no signs of liver damage. But his story may prove instructive for other prostate cancer patients who take an anti-androgen as part of their hormone therapy regimen — many of whom report that their liver function has never been tested. (For an overview of the liver, see Figure 1 below.)
Figure 1: The liver: A chemical factory
The liver is a chemical factory and storage facility for the body. It converts substances in digested food into proteins, fats, carbohydrates, and nutrients. It stores vitamins and sugars, which the body uses for energy. It manufactures cholesterol, from which the body makes hormones such as estrogen and testosterone. It helps clean the blood of impurities and creates many essential proteins, including those that help blood clot.
The mysterious case of Mr. Lincoln
After feeling a nodule on Lincoln’s prostate during a digital rectal exam (DRE) in 2005, Lincoln’s doctor suggested that his patient have a biopsy. Of the six tissue samples that were taken, only 5% of one of the cores was deemed positive for cancer. It was graded a Gleason 3 + 3. His prostate-specific antigen (PSA) level had been holding steady at 4.2 ng/ml, so while the biopsy result raised some concern, the overall findings weren’t especially worrisome.
But Lincoln wanted a second opinion, so he met with another specialist beginning in November 2005. By then, his PSA was 6.4 ng/ml, and the DRE once again proved suspicious. So in July 2006, he had a saturation biopsy, during which doctors removed 20 cores. Pathologists found cancer infiltrating between less than 5% and 75% of 14 of the cores. And the cancer was slightly more advanced than originally thought: his Gleason score increased from a 3 + 3 to a 3 + 4.
Lincoln began to consider his treatment options and ultimately chose radiation therapy because he believed that, in his case, it might better preserve urinary and sexual function. His doctor recommended starting hormone therapy in advance of radiation. I endorse this practice in patients with a Gleason component of 4 or with a tumor that can be felt during a DRE, because, in these circumstances, patients live longer following combination therapy than radiation alone. I prescribe hormone therapy until the PSA reaches its lowest point, or nadir, and stays at that level for a month. It usually takes two to four months to reach nadir. The patient then undergoes radiation therapy.
Lincoln’s doctor prescribed a combined androgen blockade, which involves two drugs to block all the activity of testosterone — one that acts centrally on the brain to stop testosterone production (an LHRH agonist) and another (an anti-androgen) that acts at the prostate cell level to block the effects of testosterone that may still be circulating in the bloodstream. (Of note: Prescribing a combined androgen blockade is somewhat controversial. Many physicians, including me, do so because some studies show that it may confer a slight survival advantage. Others avoid the practice due to side effects, the potential for liver damage, and additional costs. For more information, see “Combined androgen blockade meta-analyses” below.)
Combined androgen blockade meta-analyses
Two large meta-analyses that reviewed many studies comparing combined androgen blockade to monotherapy (using either surgery or LHRH agonists alone) concluded that the combination offered only a small survival advantage — and even that finding was inconsistent.
SOURCES: Prostate Cancer Trialists’ Collaborative Group. Maximum Androgen Blockade in Advanced Prostate Cancer: An Overview of the Randomized Trials. Lancet 2000;355:1491–98. PMID: 10801170.
Samson DJ, Seidenfeld J, Schmitt B, et al. Systemic Review and Meta-Analysis of Monotherapy Compared with Combined Androgen Blockade for Patients with Advanced Prostate Carcinoma. Cancer 2002;95:361–76. PMID: 12124837.
Since the approval of the first anti-androgen, flutamide (Eulexin), in 1989, reports of patients experiencing hepatitis, impaired liver function, and liver failure have periodically made their way into medical journals. (See “Early reports of liver toxicity” below.) But these potential side effects aren’t unique to flutamide. The two other anti-androgens — bicalutamide and nilutamide (Nilandron) — can also irritate the liver, prompting a rise in certain liver enzymes in up to 13% of patients, depending on the drug.
Although the reporting of adverse drug reactions is voluntary, meaning that not every case is recorded, serious liver problems appear rare: in one report, the FDA noted that 20 patients died and 26 others were hospitalized due to liver toxicity linked to flutamide between February 1989 and December 1994. That translates to a rate of approximately three cases for every 10,000 flutamide users, which is not many. Even so, that is 10 times greater than the expected rate of acute, noninfectious liver injuries in men ages 65 and older.
Early reports of liver toxicity
Early reports focused on flutamide; other anti-androgens weren’t approved by the FDA until the mid-1990s.
SOURCES: Hart W, Stricker BH. Flutamide and Hepatitis. Annals of Internal Medicine 1989;110:943–44. PMID: 2719431.
Rosenthal SA, Linstadt DE, Leibenhaut MH, et al. Flutamide-Associated Liver Toxicity During Treatment with Total Androgen Suppression and Radiation Therapy for Prostate Cancer. Radiology 1996;199:451–55. PMID: 8668793.
Wysowski DK, Fourcroy JL. Flutamide Hepatotoxicity. Journal of Urology 1996; 155:209–12. PMID: 7490837.
Wysowski DK, Freiman JP, Tourtelot JB, Horton ML 3rd. Fatal and Nonfatal Hepatotoxicity Associated with Flutamide. Annals of Internal Medicine 1993;118:860–64. PMID: 7683180.
Early liver function tests
In these early case reports and scientific studies, physicians and researchers declared that patients should have liver function tests during anti-androgen therapy, but didn’t specify how often. Current product labeling on file with the FDA says that liver function tests should be completed before patients start the drugs, and then given every month for the first four months, and periodically after that. However, patients have been referred to me who were already taking an anti-androgen and hadn’t had a single liver function test.
Because studies have shown that liver toxicity generally occurs early on, usually within the first few months, I recommend a slightly different testing schedule. In addition to baseline studies, I suggest checking liver function ever two weeks for the first two months, followed by monthly testing for as long as the patient is taking the anti-androgen. This allows me to spot a potential problem early on. Without periodic testing, a patient and his doctor might not notice a worsening liver problem until the patient’s skin and the whites of his eyes develop a yellow tone, a condition called jaundice, and his urine turns dark. By this time, liver damage might be difficult to reverse.
For prostate cancer patients taking an anti-androgen as part of combined hormone therapy, liver function tests should assess five items:
- ALT, short for alanine transaminase
- AST, short for aspartate transaminase
- LDH, short for lactic dehydrogenase
- alkaline phosphatase
The first four are enzymes; bilirubin is a component of digestive juices. All are produced in the liver, and elevated levels of any of them may indicate liver damage or injury to liver cells. Of the five, bilirubin is usually the last to become elevated, so relying on a bilirubin test or waiting to see if the patient develops jaundice may mean that liver problems will become advanced before they are detected.
Thinking that his patient might need a combined androgen blockade, Lincoln’s physician ordered blood tests to assess his liver function and establish baseline readings in early 2006 (see Table 1). After Lincoln started taking the LHRH agonist and the anti-androgen on Aug. 24, 2006, he had blood tests every two weeks to check his liver enzymes. The first test, in early September, showed normal liver function. (This particular test was done at a different hospital and is not listed in Table 1.) But by the third week in September, Lincoln’s ALT, AST, and LDH levels had jumped dramatically, prompting his doctor to stop the anti-androgen immediately. Over the course of the next several months, his liver enzymes gradually returned to their normal levels. (In most cases, liver enzyme levels return to normal more quickly than this.)
Table 1: Results of Lincoln’s liver function tests
Normal levels are shown for four key liver enzymes and bilirubin. Three consecutive test results show that Lincoln had normal liver function when he started bicalutamide on Aug. 24, 2006. But one month later, some of his enzyme levels had skyrocketed, prompting the discontinuation of the drug.
|ALT (alanine transaminase)||AST (aspartate transaminase)||LDH (lactic dehydrogenase)||Alkaline phosphatase||Bilirubin|
|Normal levels||0–40 IU/L||0–40 IU/L||94–250 IU/L||39–117 IU/L||0–1.5 mg/dL|
|Feb. 9, 2006||24||19||156||56||0.4|
|July 27, 2006||18||17||142||56||0.5|
|Aug. 24, 2006||18||18||151||70||0.4|
|Sept. 21, 2006||624||281||235||63||0.6|
|Oct. 19, 2006||313||131||213||70||0.5|
|Nov. 16, 2006||113||53||154||66||0.5|
|Dec. 14, 2006||64||33||201||70||0.4|
|Feb. 22, 2007||33||23||161||74||0.5|
In most cases, patients who stop taking an anti-androgen can continue to take other medications that they need, unless the drugs might affect the liver. For prostate cancer patients who are on hormone therapy, like Lincoln, there is no need to stop the LHRH agonist. Leuprolide helped drop his PSA level to 0.1 ng/ml by mid-October, and he started radiation therapy the next month. And, at least for now, his cancer shows no signs of recurrence.
One note of caution: If your physician wants to assess baseline liver function or prescribe anti-androgens in conjunction with an LHRH agonist, do not drink any alcohol. Because the liver handles detoxification, any alcohol in your system may confound test results or worsen liver problems. And be sure your doctor knows about any medications and supplements you take, as they may also affect test results.
Most cases of liver toxicity aren’t nearly as dramatic as Lincoln’s, and the majority of patients never have any trouble. In my practice, I probably see only one patient a year who has a reaction like Lincoln’s, and only about 5% of my patients experience elevated liver enzymes while taking an anti-androgen. But as a patient, you need to be your own advocate. Many physicians aren’t aware of the potential for liver trouble, so if yours prescribes an anti-androgen, press for frequent liver function tests and report any symptoms, such as nausea, vomiting, or jaundice, immediately.
Originally published July 2009; last reviewed March 16, 2011.