Hormone therapy for prostate cancer

Marc B. Garnick, M.D.,* discusses the options and controversies

Androgens, the family of male sex hormones that includes testosterone, function as a fuel for growth — a quality that explains their central role in both normal development and prostate cancer. In adolescent boys, androgens not only trigger sexual development, but also contribute to a deeper voice, a beard, and increased muscle strength and bone mass. When prostate cancer develops, however, this androgen fuel contributes to tumor growth and progression.

About 90% to 95% of androgens are produced in the testicles, while another 5% to 10% are produced by the adrenal glands. Androgen-deprivation therapy, more commonly known as hormone therapy, is one of the most powerful weapons in the fight against prostate cancer because it significantly reduces the fuel supply that is feeding malignant growth. Hormone therapies now available target testosterone production by the testicles or androgen’s activity in the body.

First developed in the 1940s, based on studies by Dr. Charles Huggins and other researchers at the University of Chicago, hormone therapy produced such dramatic early results that investigators thought they had found a way to cure prostate cancer. Unfortunately, long-term clinical trials later showed what we now know to be the case: Eventually prostate cancer becomes resistant to androgen-deprivation therapy and progresses.

We don’t know yet why men with prostate cancer develop androgen resistance, but a leading theory is that prostate tumors contain different types of cells, some of which are resistant to hormone treatment. Eventually, these resistant prostate cancer cells multiply and the disease advances. But even if it doesn’t cure prostate cancer, hormone therapy can keep it at bay for years. In fact, one of my patients has now been on some type of hormone therapy for nearly 16 years.

Once reserved solely as a treatment for metastatic prostate cancer, hormone therapy is now also used in a variety of other ways. And medication options — in terms of both the number of drugs available and choices about the timing and duration of therapy — have also evolved and improved.

This article serves as a basic primer about hormone therapy for prostate cancer. It explains when to consider hormone therapy, what your options are in terms of drugs or combinations of drugs, and what you should know about side effects. Finally, it explores several controversies currently being debated by medical experts, and where I stand on these issues. (If you’d like to learn more on your own, see “History and overviews of hormone therapy.”)

When to consider hormone therapy

Hormone therapy is a treatment option for men with prostate cancer in any of the following situations:

• when cancer has metastasized beyond the prostate
• when cancer is confined to the prostate, but hormone therapy is used to boost the effectiveness of radiation therapy or to shrink the size of a tumor before brachytherapy
• when PSA begins to rise sometime after initial treatment with surgery or radiation therapy, indicating the cancer may have recurred.

Not all doctors agree on when to use hormone therapy, or how to administer it. Indeed, this is an area that requires a physician to exercise as much art as science in clinical practice. You should also be aware that side effects can be daunting, although most men tolerate treatment reasonably well (see “Side effects of hormone therapy”).

Systemic therapy for metastatic disease

The most common use of hormone therapy today is to treat men whose prostate cancer has metastasized to other parts of the body. If prostate cancer cells escape the prostate, they migrate first to surrounding structures, such as the seminal vesicles and lymph nodes, and later to the bones or, rarely, to other soft tissues.

Hormone therapy is recommended as a palliative treatment, to relieve symptoms such as bone pain. And while hormone therapy is not a cure, in that it can’t eliminate prostate cancer completely, it often extends life for many years. By reducing testosterone levels, hormone therapy can shrink a prostate tumor and its metastases and slow further progression of the cancer for so long that sometimes a man with this disease dies of something other than prostate cancer.

Traditionally, doctors believed that it was best to prescribe hormone therapy as soon as metastatic prostate cancer is discovered, and advised patients to continue hormone therapy for the rest of their lives. Although this strategy extended the lives of many men, concerns about quality-of-life issues sparked a number of studies in which researchers tried to determine if men with metastatic disease that was only detectable in lymph nodes or on bone scans — but was not yet causing symptoms — could delay hormone therapy. For example, if a man had only one or two bone lesions, but no pain and no risk to the spinal cord, was there any benefit to waiting until he actually experienced pain from the cancer before beginning treatment?

Most studies that have looked at this question, however, concluded that starting hormone therapy early on, right after discovery of metastases, achieved better outcomes, even in men whose disease had spread only to the lymph nodes. For example, one small but often-cited study, published in 1999 in the New England Journal of Medicine, found that 77% of men who had prostate cancer with lymph node metastases and chose to undergo hormone therapy were still alive and had no recurrent disease roughly seven years later, as compared with only 18% of men who decided to forgo hormone treatment until the cancer spread to bones or lungs. A more recent analysis by the same group of researchers found that these trends held up over time (see Table 1).

Other studies have shown that starting hormone therapy early on increases survival times, delays cancer progression, and results in better quality of life. However, in a review of four studies involving 2,167 men with metastatic prostate cancer, the Cochrane Collaboration (a prestigious international organization known for its independent analysis) concluded that early hormone therapy had offered only a small overall survival advantage over deferred treatment, and cautioned that more research on the issue needs to be done.

Although debate on this issue continues, in most cases I advise my patients with metastatic disease to begin hormone treatment early on. This is particularly important for someone with spine metastases, because a bone fracture or extension of the cancer into the spinal cord area could lead to impaired mobility and even paralysis. Fortunately, this is a rare event. (For more information about research in this area, see “Hormone therapy: Immediate versus delayed.”)

Neoadjuvant and adjuvant hormone therapy for early-stage or regionally advanced disease

Hormone therapy is sometimes given in conjunction with a definitive prostate cancer treatment, such as radiation therapy, in order to improve health outcomes. When hormone therapy is given in advance of a primary treatment, it’s known as neoadjuvant therapy; when it’s given during or after a primary treatment, it’s known as adjuvant therapy.

Combined with radiation therapy. A number of studies have shown that men with early-stage prostate cancer are more likely to be cured when hormone therapy is given in conjunction with radiation therapy (see Table 2 above for the results of one study). Even when the disease is regionally advanced, meaning that it has progressed to tissues immediately surrounding the prostate gland, neoadjuvant hormone therapy reduces risk of progression and relapse (see “Evidence for combining hormone therapy and radiation treatment”).

Although we don’t understand this phenomenon completely, animal studies suggest that a dose of radiation is more effective at killing cancer cells when given in the setting of androgen deprivation. One leading theory about why this occurs is that the combination of radiation therapy and hormone therapy somehow activates the immune system, so that immune system cells attack and kill cancer cells.

Hormone therapy may also be used for anywhere from three to six months prior to brachytherapy when a man’s prostate gland is large, usually defined as bigger than 50 grams. In this situation, neoadjuvant hormone therapy is used to shrink the prostate gland to enable better implantation of radioactive seeds so that the right dose of radiation can be administered.

Combined with radical prostatectomy. The results of combining hormone therapy and surgery have been mixed. On the one hand, neoadjuvant hormone therapy is effective at “down-staging” the disease before surgery by shrinking the primary tumor and eradicating micrometastases. Short-term studies were encouraging, showing that neoadjuvant hormone therapy reduced the risk of finding a positive margin in the excised tissue. On the other hand, long-term studies indicate that neoadjuvant hormone therapy does not extend time to biochemical recurrence or improve survival. (For examples of studies, see “Evidence about hormone therapy and prostatectomy.”)

Secondary treatment following relapse

Hormone therapy may also be used as a secondary or “salvage” treatment when PSA levels rise following initial prostate cancer treatment, indicating the cancer has returned. This situation is known as biochemical recurrence. The salient points to keep in mind are that hormone therapy is most often used as a salvage treatment when PSA doubling time is less than six months, indicating that the cancer is aggressive or may have already metastasized.

Options in hormone therapy

Testosterone levels in the body can be reduced either surgically or with drugs. The surgical option is castration, achieved by removing the testicles during a bilateral orchiectomy. Once the only option, it has since been supplanted by drugs that lower testosterone levels to amounts achieved by surgery.

For men, normal testosterone levels range from 300 to 1,000 ng/dl. The FDA requires that any new drug used in hormone therapy for prostate cancer lower testosterone levels to 50 ng/dl or less. In my practice, I usually try to lower levels even further, to 20 ng/dl.

Orchiectomy

Because more than 90% of androgens are produced in the testicles, bilateral orchiectomy significantly reduces testosterone levels in the body. The operation can be done on an outpatient basis. The surgeon opens the scrotum, and then removes the testicles, while preserving blood vessels and nerves. If a man is concerned about how his genitals will look after the operation, it is possible to have the surgeon insert saline implants into the scrotum, which will look and feel like testicles. Often, though, the spermatic cord is still present as well as some surrounding testicular structures, thus preventing the appearance of an “empty scrotum.”

Although the operation is relatively simple, many men find it psychologically devastating to lose their testicles — and for this reason alone decide against it. Another factor to consider is that, unlike medication options, orchiectomy is permanent. Some men continue to choose this option, however, because it remains the most efficient way to reduce testosterone levels, and it eliminates expenditures on medications and multiple visits for monitoring side effects that would be needed to achieve the same results. The option of orchiectomy is also sometimes recommended for elderly men who cannot readily visit a doctor for an injected medication, or who cannot risk the cardiovascular side effects of diethylstilbestrol (DES).

LHRH agonists

Luteinizing hormone-releasing hormone (LHRH) is secreted by the hypothalamus, sending the first chemical signal essential for testosterone production (see Figure 1 above). LHRH agonists are among the most popular choices for hormone therapy in prostate cancer. These drugs work centrally, on the brain. (Because LHRH is sometimes called GnRH, or gonadotropin-releasing hormone, these medications are sometimes referred to as GnRH agonists.)

LHRH agonists are listed in Table 3 below. Because these medications are peptides, which would be broken down in the digestive system if taken by mouth, they cannot be given in pill form. Instead, LHRH agonists are injected into a muscle or fat tissue under the skin. The first LHRH agonists were self-injected on a daily basis by patients, much like insulin. But today “depot” formulations are available, which can be implanted under the skin to provide extended release of the medication. Such depot formulations can be given anywhere from once every four weeks to once a year.

LHRH agonists are popular because they don’t cause as many cardiovascular problems and other side effects as DES does. Even so, research indicates that using these medications can increase total cholesterol and triglyceride levels, as well as blood sugar levels and risk of diabetes, all of which can increase risk of having a heart attack (see “Cardiovascular risk,” below). To ensure that you can take these drugs safely, your doctor will measure your blood sugar and cholesterol levels, and may recommend an exercise stress test to determine your overall heart health.

LHRH agonists also cost more than DES and require more frequent physician visits. More significantly, LHRH agonists cause a temporary surge in testosterone, generally lasting about three weeks to a month, which fuels prostate cancer growth. Although the cancer will regress once the surge ends and testosterone levels plummet, LHRH agonists are usually given in conjunction with anti-androgens — especially in men whose disease has metastasized to the spine, to prevent paralysis.

The testosterone surge is caused by the way these drugs act on LHRH receptors. As explained in Figure 1, the LHRH receptor normally receives only pulsating hits of LHRH. But the synthetic version of this hormone used in drug formulations remains “plugged in” to the receptor, so that it cannot turn off. It’s like leaving the toaster in the “on” position permanently: Initially you generate a lot of heat, but eventually you burn out the coils. Similarly, by taking LHRH agonists, men rev up the testosterone production system and eventually wear it out. (This temporary surge is actually valued by fertility experts, who use these drugs today for in vitro fertilization.)

GnRH antagonist

A new type of drug, abarelix (Plenaxis), received FDA approval in 2003, but for commercial reasons is currently not being promoted or available to new patients in the United States. However, the drug recently received regulatory approval in Germany, so that it may be available in Europe by the end of 2007.

Abarelix is a GnRH antagonist, which targets receptors in the pituitary gland and shuts them off without the obligatory initial stimulation characteristic of agonists. As such, it avoids triggering the testosterone surge created by LHRH agonists. (For more information about this medication, see “Research on abarelix.”)

This medication is injected into the buttocks muscle every two weeks for the first month, then afterward once every four weeks. Because there is a small chance that men receiving abarelix may experience an allergic reaction, causing low blood pressure and fainting, patients need to remain in the physician’s office for 30 minutes after the injection to ensure that such a reaction does not occur, or if it does, can be treated promptly.

Anti-androgens

Orchiectomy, DES, LHRH agonists, and the GnRH antagonist all work by shutting down production of testosterone in the testes. But about 5% to 10% of male hormones are produced in the adrenal glands. These androgens, which are closely related to testosterone, can also be converted to DHT and promote prostate cancer growth.

Because anti-androgens target receptors at the cellular level, rather than in the brain, they are classified as peripherally acting medications. This class includes flutamide (Eulexin), bicalutamide (Casodex), and nilutamide (Nilandron). The drug most often used is bicalutamide, which is given once a day and is less likely than the others to cause diarrhea.

Anti-androgens are often given in conjunction with LHRH agonists in order to counter the effects of the testosterone surge described earlier. But this use is controversial (see “Combined androgen blockade: Pro and con” below). Anti-androgens may also be prescribed if an orchiectomy or LHRH agonist is unable to keep testosterone levels at sufficiently low levels.

Estrogen

Diethylstilbestrol was the first type of drug used in hormone therapy for prostate cancer, and it remains in very limited use today — albeit with dosing changes, and not as a first choice. DES is a synthetic form of the female hormone estrogen. It is effective at lowering testosterone levels because it inhibits secretion of LHRH from the hypothalamus (see Figure 1).

Unfortunately, at moderate to high doses, such as 5 mg per day, DES causes significant cardiovascular problems and raises the risk of having a heart attack. To reduce this risk, physicians may try to reduce the dose to 1 mg per day, but this causes another problem: At this dose, testosterone levels often begin rising after 6 to 12 months of treatment. Today, DES is usually prescribed at 3 mg per day.

This medication is prescribed to men who value the convenience of taking an inexpensive drug once a day. Some physicians recommend taking a baby aspirin once a day to reduce risk of cardiovascular problems, but no studies have been conducted to provide evidence that this works. On the other hand, men do have options for dealing with another common side effect of DES, gynecomastia.

Controversies in hormone therapy

The use of hormone therapy requires as much art as science. Physicians do not always agree about when it is best to start treatment, whether it needs to be continuous or can be stopped and started up again periodically, and whether monotherapy or combination therapy is best. Here are the salient issues, what the studies say — and what I believe and follow in my own practice.

Initiation of therapy

We’ve already covered the longstanding debate about whether to initiate hormone therapy early or late after discovery of metastases. As the use of hormone therapy has expanded to other situations, questions about when to initiate therapy may also come up.

For use as neoadjuvant and adjuvant therapy. Your doctor may recommend hormone therapy before, during, and after radiation treatment. Few guidelines exist about exactly when to initiate hormone therapy and how long to continue it. Options abound, and the studies cannot cover every situation. You might have

• two months of hormone therapy, followed by two months of radiation treatment combined with hormone therapy, for a total of four months
• two months of hormone therapy, two months of hormone therapy and radiation treatment, followed by two months of hormone therapy, for a total of six months
• concomitant radiation treatment and hormone therapy for two months, then hormone therapy for a total of three years.

This is an area where the art and science of medicine come into play. I select any patient with a Gleason component of 4, or palpable disease upon physical examination, who is a candidate for radiation treatment. I prescribe hormone therapy until the PSA reaches its lowest point (nadir), and that nadir is maintained for a month. It usually takes two to four months to reach nadir. Then the patient undergoes radiation treatment, while continuing hormone therapy. How long hormone therapy continues after radiation treatment ends depends on the man’s risk profile. I treat some men for a total duration of 6 months, while others may be treated for 9 months, a year, or 18 months.

For rising PSA. When PSA rises after initial treatment and the doubling time is less than six months, your doctor will likely recommend a full course of hormone therapy, which can delay progression of metastases to the bones. If PSA doubling time indicates the cancer is not aggressive, however, and you want to remain sexually active and avoid other side effects, then delaying hormone therapy while monitoring PSA may be the way to go.

Intermittent or continuous therapy

Once prescribed, hormone therapy used to continue for life, but scientists are now reevaluating that strategy and investigating whether hormone therapy can be taken intermittently, with so-called holidays from treatment. The thinking is that this may not only help restore quality of life — as, for example, returning libido and sexual health — but also delay the hormone resistance that eventually develops in men taking hormone therapy.

Clinical trials evaluating whether intermittent therapy is as effective or more effective than continuous therapy are now under way, so it is too early to say for sure.

Combined androgen blockade

Combined androgen blockade — also known as maximum androgen blockade or total androgen blockade — involves the concomitant use of a drug that acts centrally on the brain (an LHRH agonist or GnRH antagonist) and another that acts peripherally at the prostate cell level (an anti-androgen). In that way, you block all the activity of the androgens — not only production of testosterone, but also its action in the prostate itself. Theoretically, this should make hormone therapy even more effective. But combined androgen blockade is controversial.

One large controlled study, published in the New England Journal of Medicine, reported that combined androgen blockade (in this case the LHRH agonist leuprolide combined with the anti-androgen flutamide) offered roughly a 25% survival advantage over monotherapy (leuprolide alone). But a larger follow-up study, which involved surgery (instead of leuprolide), did not find any survival advantage with the addition of the anti-androgen. This study — which itself has generated some controversy — compared bilateral orchiectomy alone with orchiectomy combined with flutamide. (For more information about these studies, see “Combined androgen blockade: Pro and con.”)

Two large meta-analyses that reviewed many studies comparing combined androgen blockade to monotherapy (using either surgery alone or LHRH agonists alone) concluded that the combination offered only a small survival advantage — and even that finding was inconsistent between the two analyses. One analysis, which reviewed 27 randomized studies involving 8,275 men, estimated that combined androgen blockade improved five-year survival by only 2% to 3%, at most. (For more information, see “Analyzing the studies,” below.) However, an advantage of “only” 2% to 3%, when applied to thousands of men undergoing treatment, translates into hundreds of lives extended — obviously an important benefit to the men who gain months and even years of life as a result. That is why I use combined therapy for all of my patients who undergo hormone treatments.

Most doctors prescribe an anti-androgen a little before LHRH agonist treatment begins and then continue it for another month afterwards. In that way, anti-androgens counter the initial testosterone surge, but then are stopped when the surge is no longer a problem. What many physicians do not know is that actual levels of testosterone during the first month of combined androgen blockade are no different whether the anti-androgen is used or not. The potential benefit of the anti-androgen is to block effects of the circulating testosterone at the prostate cancer cell level.

What I recommend. Although it goes against conventional wisdom, I’m a total believer in combined androgen blockade. This is based upon both my reading of the key studies and my experience in treating patients. Take, for example, the 1989 study published in the New England Journal of Medicine (see “Combined androgen blockade: Pro,” above). Combining leuprolide with flutamide gave men with the most advanced prostate cancer another seven months to live, on average; the advantage was nearly two years for patients with less advanced metastatic disease. A potential seven-month or two-year survival edge may not seem overwhelming to a researcher, but it can be highly significant to the man affected and his family! It is also the reason why I spent a large portion of my professional life developing a GnRH antagonist that can act without the requirement for an anti-androgen.

So I tend to use anti-androgens extensively. I rarely, if ever, put a patient on LHRH monotherapy. But I don’t use combined androgen blockade for extended periods of time, because that causes another problem. If you block the DHT androgen receptor for too long with anti-androgens, something known as anti-androgen withdrawal syndrome occurs. This is a paradoxical situation in which the anti-androgen acts as an agonist — stimulating the receptors — rather than as an antagonist that blocks them. PSA levels rise, and hormone therapy stops working.

Fortunately, options still exist when anti-androgen withdrawal syndrome occurs. The first thing I do is discontinue the anti-androgen medication. The receptors are no longer stimulated, and about 25% to 30% of people will respond to the other leg of hormone therapy, LHRH agonists.

Looking ahead

Hormone therapy, long the cornerstone of treatment for metastatic prostate cancer, can also improve effectiveness of radiation therapy and provide another option for men whose rising PSA indicates a cancer relapse. As we look ahead to the future, several challenges remain in improving hormone therapy. First, we must determine how to better fine-tune the timing and duration of hormone therapy for patients, to provide optimal results. Second, we must find ways to overcome androgen resistance, so that lives can be extended even further. Finally, it’s important to find ways to reduce or at least counter side effects of hormone therapy, to lessen the impact on patients’ quality of life.

Originally published July 1, 2007; last reviewed March 22, 2011.