By R. Morgan Griffin
Reviewed By Charlotte Grayson
Hormone therapy for prostate cancer has come a long way in the past few decades. Not so long ago, the only hormonal treatment for this disease was drastic: an orchiectomy, the surgical removal of the testicles.
Now we have a number of medications -- available as pills, injections, and implants -- that can give men the benefits of decreasing male hormone levels without irreversible surgery.
"I think hormonal therapy has done wonders for men with prostate cancer," Stuart Holden, MD, Medical Director of the Prostate Cancer Foundation.
Hormone therapy for prostate cancer does have limitations. Right now, it's usually used only in men whose cancer has recurred or spread elsewhere in the body.
But even in cases where removing or killing the cancer isn't possible, hormone therapy can help slow down cancer growth. Though it isn't a cure, hormone therapy for prostate cancer can help men with prostate cancer feel better and add years to their lives.
On average, hormone therapy can stop the advance of cancer for two to three years. However, it varies from case to case. Some men do well on hormone therapy for much longer.
What Is Hormone Therapy?
The idea that hormones have an effect on prostate cancer is not new. The scientist Charles Huggins first established this over 60 years ago in work that led to his winning the Nobel Prize. Huggins found that removing one of the main sources of male hormones from the body -- the testicles -- could slow the growth of the disease.
"This procedure worked dramatically," says Holden, who is also director of the Prostate Cancer Center at Cedar Sinai Medical Center in Los Angeles. "Before, these men were confined to bed and wracked with pain. Almost immediately afterwards, they improved."
Huggins found that some types of prostate cancer cells need certain male hormones -- called androgens -- to grow. Androgens are responsible for male sexual characteristics, like facial hair, increased muscle mass, and a deep voice. Testosterone is one kind of androgen. About 90% to 95% of all androgens are made in the testicles, while the rest are made in the adrenal glands located on top of the kidneys.
How Does Hormone Therapy Work?
Hormone therapy for prostate cancer works by either preventing the body from making these androgens or by blocking their effects. Either way, the hormone levels drop, and the cancer's growth slows.
"Testosterone and other hormones are like fertilizer for cancer cells," Holden tells WebMD. "If you take them away, the cancer goes into shock, and some of the cells die."
In 85% to 90% of cases of advanced prostate cancer, hormone therapy can shrink the tumor.
However, hormone therapy for prostate cancer doesn't work forever. The problem is that not all cancer cells need hormones to grow. Over time, these cells that aren't reliant on hormones will spread. If this happens, hormone therapy won't help anymore, and your doctor will need to shift to a different treatment approach.
What Types of Hormone Therapy Are There?
There are two basic kinds of hormone therapy for prostate cancer. One class of drugs stops the body from making certain hormones. The other allows the body to make these hormones, but prevents them from attaching to the cancer cells. Some doctors start treatment with both drugs in an effort to achieve a total androgen block. This approach goes by several names: combined androgen blockade, complete androgen blockade, or total androgen blockade.
Here's a rundown of the techniques.
- Luteinizing hormone-releasing hormone agonists (LHRH agonists.) These are chemicals that stop the production of testosterone in the testicles. Essentially, they provide the benefits of an orchiectomy for men with advanced prostate cancer without surgery. This approach is sometimes called "chemical castration." However, the effects are fully reversible if you stop taking the medication.
Most LHRH agonists are injected every one to four months. Some examples are Lupron, Trelstar, Vantas, and Zoladex. A new drug, Viadur, is an implant placed in the arm just once a year.
Side effects can be significant. They include: loss of sex drive, hot flashes, development of breasts (gynecomastia) or painful breasts, loss of muscle, weight gain, fatigue, and decrease in levels of "good" cholesterol.
Plenaxis is a drug that's similar to LHRH agonists. However, because it can cause serious allergic reactions, it's not used that often.
- Anti-androgens. LHRH agonists and orchiectomies only affect the androgens that are made in the testicles. Thus they have no effect on the 5% to 10% of a man's "male" hormones that are made in the adrenal glands. Anti-androgens are designed to affect the hormones made in the adrenal glands. They don't stop the hormones from being made, but they stop them from having an effect on the cancer cells.
The advantage of anti-androgens is that they have fewer side effects than LHRH agonists. Many men prefer them because they are less likely to diminish libido. Side effects include tenderness of the breasts, diarrhea, and nausea. These drugs are also taken as pills each day, which may be more convenient than injections. Examples are Casodex, Eulexin, and Nilandron.
In some cases, starting treatment with an LHRH agonist can cause a "tumor flare," a temporary acceleration of the cancer's growth due to an initial increase in testosterone before the levels drop. This may cause the prostate gland to enlarge, obstructing the bladder and making it difficult to urinate. It's believed that starting with an anti-androgen drug and then switching to an LHRH agonist can help avoid this problem. In patients with bone metastases, this "flare" can lead to significant complications such as bone pain, fractures, and nerve compression.
Strangely, if treatment with an anti-androgen doesn't work, stopping it may actually improve symptoms for a short time. This phenomenon is called "androgen withdrawal," and experts aren't sure why it happens.
- Combined Androgen Blockade. This approach combines anti-androgens with LHRH agonists or an orchiectomy. By using both approaches, you can cut off or block the effects of hormones made by both the adrenal glands and the testicles. However, using both treatments can also increase the side effects. An orchiectomy or an LHRH agonist on its own can cause significant side effects like a loss of libido, impotence, and hot flashes. Adding an anti-androgen can cause diarrhea, and less often, nausea, fatigue, and liver problems.
- Estrogens. Some synthetic versions of female hormones are used for prostate cancer. In fact, they were one of the early treatments used for the disease. However, because of their serious cardiovascular side effects, they're not used as often anymore. J. Brantley Thrasher, MD, a spokesman for the American Urological Association and chairman of urology at the University of Kansas Medical Center, says they're usually used only after initial hormone treatments have failed. Examples of estrogens are DES (diethylstilbestrol), Premarin, and Estradiol.
- Other Drugs. Proscar (finasteride) is another drug that indirectly blocks an androgen that helps prostate cancer cells grow. Depending on the case, doctors sometimes use other anticancer drugs like Nizoral (ketoconazole) and Cytadren (aminoglutethimide.)
- Orchiectomy. The surgical removal of the testicles was the earliest form of hormone therapy for prostate cancer. However, the procedure is permanent. As with LHRH agonists, side effects can be significant. They include: Loss of sex drive, hot flashes, development of breasts (gynecomastia) or painful breasts, loss of muscle, weight gain, fatigue, and decrease in levels of "good" cholesterol.
"Since we have other options, orchiectomies really aren't done very much anymore," says Holden.
However, it can be the right choice in certain cases. "Some men might get the procedure because they're tired of getting shots and aren't sexually active anyway," says Thrasher. "Or they may have financial concerns. In the long-run, an orchiectomy is much cheaper than LHRH agonists."
Hormone therapy for prostate cancer can cause bone thinning osteoporosis, which can lead to broken bones. However, treatment with bisphosphonates -- like Aredia, Fosamax, and Zometa -- may help prevent this condition from developing, says Holden.
What Type of Hormone Therapy Works Best?
Unfortunately, understanding the details of hormone therapy for prostate cancer can be difficult. Which drug or combination of drugs works best? In what order should they be tried? Research hasn't answered these questions yet.
"Right now, there's a level of art to figuring out which agents to use," says Durado Brooks, MD, MPH, director of prostate cancer programs at the American Cancer Society. "We don't have clear evidence yet."
LHRH agonists remain the usual first treatment. But in some cases, doctors are trying anti-androgens first. Anti-androgens may be especially appealing to younger men who are still sexually active, since these drugs don't completely shut down sex drive. When anti-androgens stop working -- based on PSA tests -- a person then might shift onto an LHRH agonist.
Other doctors prefer to begin therapy with a combination of two or even three drugs, especially for patients with symptoms or advanced disease, says Holden.
Researchers originally hoped that combined androgen blockade would significantly add to the benefits of LHRH agonists. However, the results, to date, have been mixed. Some studies have shown slightly longer survival with combined androgen blockade, but the results haven't been as dramatic as many experts had hoped. Other studies have shown no benefit. A possible explanation may be the type of anti-androgen used, but further studies are needed to answer this question.
"I think early on, there was hope that it would have a more profound effect," Thrasher tells WebMD.
Brooks agrees. "I think that anti-androgens have made a significant difference in terms of quality of life for men with advanced prostate cancer," says Brooks. "However, we haven't really seen proof that they let people live longer" when combined with LHRH agonists.
Different Approaches to Starting Hormone Therapy
Experts debate how early treatment with hormone therapy should be started. Some argue that the benefits of hormone therapy for prostate cancer should be offered to men earlier in the course of the disease. Others assert that there's little evidence that getting treatment early is better than getting it later.
"Unfortunately, there are still some doctors who are offering hormonal therapy earlier in the course of the disease than is commonly recommended," Brooks says. Given that the side effects can be serious, Brooks argues that starting treatment with hormone therapy so early may not be a good idea.
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However, Holden argues that early treatment may be helpful. "I think one of the reasons that the death rate from prostate cancer is going down is that we're using hormone therapy early," he tells WebMD. "We haven't proved that early treatment improves overall survival yet, but I think we will."
Researchers are also looking at "intermittent therapy," starting and stopping hormone treatment for months at a time. The big advantage is that men could go off therapy temporarily and thus be free of the side effects. Early study results have been promising.
Hormone therapy for prostate cancer is also being tested in combination with other therapies, like radiation and chemotherapy. One recent study looked at men with locally advanced prostate cancer - cancer that has spread outside the prostate, but not yet into other parts of the body. Researchers found that adding just six months of hormone therapy to radiation allowed the men to live longer. Researchers are also studying the effects of hormone therapy earlier in treatment, for instance right after or even before surgery.
The Future of Hormone Therapy for Prostate Cancer
Some experts aren't sure how much further we can improve hormone therapy for prostate cancer.
"I'm not saying that we've reached the end of what we can do with hormonal therapy," Thrasher tells WebMD, "but there are only so many ways to shut down the hormonal effects. The cancer will still eventually escape."
Brooks argues that, overall, prostate cancer is only moderately affected by hormones. "You can only do so much manipulating the levels of hormones," says Brooks. "We have to find better ways to fight the basis of the cancer cells."
Thrasher and Brooks have more hope that the next breakthroughs will come with different approaches, like chemotherapy or vaccines.
But Holden remains optimistic about the future of hormone therapy for prostate cancer.
"Cancer cells eventually figure out how to survive, how to overcome a specific hormone therapy," he says. "But if we have enough types of drugs and can keep changing the hormone therapy, we might be able to keep the cancer cells in a state of confusion. We could change therapies before they have a chance to adapt."
"It's like an endless chess game," he says. "You may not ever win, but you might be able to prolong the game indefinitely. I think that hormone therapy still has a lot of promise. We just need to develop better anti-androgens, and more varieties of them."
While experts debate the best way to use hormone therapy for prostate cancer, they do agree on the strides we've made in treating this disease. Improved detection and treatment -- like hormone therapy -- have really changed the picture.
"Prostate cancer is really a different disease than it was 15 years ago," says Thrasher. "Men who have recurrent prostate cancer are living so much longer than they used to."
Published May 2005.
SOURCES: Durado Brooks, MD, MPH, director of prostate cancer programs, American Cancer Society. Stuart Holden, MD, medical director, Prostate Cancer Foundation; director, Warschaw Prostate Cancer Center, Cedars Sinai Medical Center, Los Angeles. J. Brantley Thrasher, MD, William L. Valk Chair of Urology, head of the department of urology, University of Kansas Medical Center, Kansas City; spokesman, American Urological Association. American Urological Association UrologyHealth web site. American Cancer Society. National Cancer Institute.
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