By: Mark Scholz, M.D.
Prostate Oncology Specialists
Traditionally, anti-androgen medications have been used in combination with LHRH agonists to block testosterone. When anti-androgens are used alone, as so-called anti-androgen monotherapy, it causes in a milder degree of testosterone blockade. There are three anti-androgens—bicalutamide, flutamide, and nilutamide. They work by keeping testosterone away from the androgen receptor, an enzymatic “switch” inside the prostate cancer cell. This switch stimulates cell growth when it’s turned on. Anti-androgens keep the switch “off.” Because anti-androgens don’t eliminate testosterone altogether, they have fewer side effects than the LHRH agonists, Lupron®, Trelstar®, Eligard® and Zoladex®.
Quality of Life
Whenever the action of testosterone is inhibited, side effects ensue. Hot flashes, osteoporosis, loss of muscle and loss of libido are typical. Many other side effects can also occur. See the article, Preventing the Side Effects of Testosterone Inactivating Pharmaceuticals at www.pcri.org for further details. Anti-androgen monotherapy (AAM) is less likely to induce muscle loss and less likely to reduce libido than the LHRH agonists. For example, only about 50% of younger men on AAM lose their libido whereas about 80% of men lose their libido with LHRH agonists.
There is one side effect that is more common with AAM than with LHRH agonists—breast enlargement. The medical term is gynecomastia. Gynecomastia occurs in 10 –20 % of men treated with LHRH agonists and in 50-60% of men on AAM. Gynecomastia can be prevented with radiation or an estrogen blocking pill called Femara®. However, once breast tissue develops, it can only be removed with liposuction or surgery. To be effectively prevented, the radiation or the Femara must be started prior to AAM.
Casodex and Flutamide
Amongst the anti-androgens, Casodex® (bicalutamide) is the preferred choice. It is often used at a dose of 150 mg (three 50 mg pills) daily. Another alternative is flutamide (Eulexin®) which is less expensive. Flutamide needs to be taken two or three times a day. Other disadvantages are a higher incidence of diarrhea and/or liver enzyme abnormalities. With appropriate expert medical supervision, these side effects are manageable. Flutamide is typically utilized when Casodex is poorly tolerated or when cost savings are paramount.
Length of Life
The attraction of AAM is fewer side effects. But to what degree do we sacrifice anti-cancer effectiveness and long-term survival? Studies performed to answer to this question have various flaws. For example, low-dose Casodex (50 mg daily) has been compared with LHRH agonists in men with advanced metastatic prostate cancer. Survival was shorter in men treated with low-dose Casodex compared to men who received Lupron or Zoladex.1,2,3,4
Higher doses of Casodex (150 mg daily) have been compared with Zoladex, a LHRH agonist, in men with fairly advanced cancer that had not quite yet spread to the bones.5 After six years, men treated with Zoladex lived an average of 6 months longer than the men treated with Casodex 150 mg a day. However, the statisticians who reviewed the trial were concerned that the study evaluated an insufficient number of men to be conclusive. Therefore, the six month difference was of questionable relevance. The difference in survival between the two groups was more likely to be due to random causes rather than the superior action of the Zoladex. Another study comparing an anti-androgen with the combination of an anti-androgen plus a LHRH agonist has been faulted for the same weakness, insufficient number of patients. In this study Casodex 150 mg a day was compared with Zoladex and flutamide men with very advanced disease that had spread to the bones.6 The side-effects of AAM are less than with LHRH agonists. However, in regards to anti-cancer effectiveness, it is possible, even likely, that AAM is somewhat less effective in controlling cancer than the LHRH agonists.
LHRH agonists should be considered standard when cure is the goal. For example, when testosterone blockade is given in conjunction with surgery or radiation or when younger patients relapse soon after surgery or radiation with fast PSA doubling times. On the other hand, anti-androgen monotherapy is a good choice for older patients or men who are less tolerant of side effects and need milder treatment to maintain quality of life.
1. Single-agent therapy with bicalutamide: a comparison with medical or surgical castrations in the treatment of advance prostate cancer. Urology 46: 849, 1995.
2. Randomised study of Casodex 50 mg monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. Scand J Urol Mephrol 30:93, 1996
3. Randomised study of Casodex 50 mg monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. European Urology 28:215, 1995.
4. A controlled trial of bicalutamide versus castration in patients with advance prostate cancer. Bales, Urology 47:38, 1996.
5. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of follow up. Journal of Urology 164: 1579.
6. Bicalutamide monotherapy versus Flutamide plus goserelin in prostate cancer patients: results of an Italian prostate cancer project study. Journal of Clinical Oncology 17:2027, 1999.