Hormone Therapy for Prostate Cancer

Hormone therapy and prostate cancer

Prostate cancer is fueled by testosterone, a hormone produced in the testicles. (See the section on testosterone below.) The aim of HT is to interfere with either testosterone production or cancer cells' ability to use testosterone. Medical evidence tells us that eliminating or substantially reducing testosterone production has a significant impact on controlling progression of the disease – and may even halt progression. Testosterone is one of several hormones called androgens that are linked to sexual health and other processes in the body. This is why HT is often referred to as androgen deprivation therapy (ADT).

To be clear, this is not the "hormone therapy" of which you often hear. Women get "hormone therapy" to supplement waning estrogen levels, and older men without prostate cancer may get "hormone therapy" that administers additional testosterone. The "hormone therapy" we are talking about for men with prostate cancer is more accurately described as androgyn deprivation therapy (ADT). It is given to lower testosterone levels.

Kinds of hormone therapy

Hormone therapy is a category encompassing a number of treatments. In some conditions or diseases, certain hormones are prescribed in order to increase their levels. This is frequently referred to as hormone replacement therapy (HRT). Hormones can be natural (endogenous) or synthetic, meaning produced commercially (exogenous). Patients who do not have prostate cancer but have symptoms from low testosterone levels, such as fatigue, may be prescribed testosterone as a type of HRT. In certain cases, patients with prostate cancer under control may receive this type of hormone therapy; however, because of the risk of activating the cancer, some doctors advise against it. Male children or adults with hypogonadism (failure of the testes to function properly) are prescribed testosterone as HRT.

As mentioned previously, HT in prostate cancer aims to reduce production of the hormone testosterone, rather than increase it, thereby interfering with cancer cells' ability to use it to grow.

The hormone therapies that have become standard prostate cancer treatments are the ones we discuss in detail in this guide. All decisions regarding these treatments should be carefully made by the patient and doctor together.

When hormone therapy is indicated

HT can be administered before, during or after a localized treatment, such as radical prostatectomy, radiation, high-intensity focused ultrasound (HIFU) or cryotherapy. When given before a localized treatment, it is called neoadjuvant therapy. When given after localized treatment without evidence of prostate cancer recurrence, it is called adjuvant therapy. When HT is prescribed after localized treatment for a prostate cancer recurrence, it is called salvage therapy. If a patient's PSA starts rising after a radical prostatectomy, HT is typically given in combination with radiation therapy. Treatment recommendations are based on each patient's specific circumstances.

Sometimes we give neoadjuvant HT while the patient is deciding on his primary treatment or to reduce the tumor's size before starting primary treatment. Neoadjuvant HT will usually slow or stop cancer growth for a period of time.

Many radiation oncologists use HT along with radiation treatment in the belief that HT weakens cancer cells so that they're more susceptible to destruction by the radiation. Clinical studies have suggested a synergy between radiation therapy and hormone therapy – meaning they work better together. Clinical trials have shown improved outcomes for patients who receive combined therapy.

When hormone therapy is recommended

Hormone therapy is typically given to patients with intermediate- or high-risk prostate cancer. It may be used in the following ways:

• In combination with radiation, mostly for patients with high Gleason scores or other high-risk factors.
• After radiation or surgery when PSA rises, indicating a recurrence.
• As therapy for patients unsuitable for radiation or surgery.
• As therapy for metastatic prostate cancer (when the cancer has spread outside the prostate gland to other sites in the body, such as distant lymph nodes or bones). It may be given instead of or in combination with chemotherapy.

HT is usually not prescribed for:

• Patients choosing a localized treatment for low-risk prostate cancer
• Low-risk patients preferring to monitor their cancer on an active surveillance program

HT may be an option for patients who are not candidates for surgery, radiation or other localized treatment because of age, pre-existing health conditions or concerns about potential side effects of localized treatments.

Testosterone

Testosterone production naturally increases during puberty as part of male growth and development. This is responsible for male sexual maturity and fertility. Increasing levels of testosterone lead to:

• Greater muscle mass
• More body and facial hair
• Deepening of the voice
• Lengthening of the penis
• Enlargement of the testicles
• Increased libido (sexual desire)
• The ability to achieve and maintain an erection
• Development of the prostate gland, which begins producing fluids that are part of semen

The first step in testosterone production occurs in the brain, when a gland called the hypothalamus sends a message to another gland in the brain called the pituitary gland. The pituitary gland then sends out a message that tells the testicles to make testosterone. Some hormone therapy drugs, (Lupron and Firmagon), lower testosterone by blocking the pituitary from sending out such messages. Small amounts of testosterone are also produced in the adrenal glands, located just above the kidneys.

How testosterone helps prostate cancer grow

Testosterone travels through the bloodstream and eventually reaches prostate cancer cells, where it helps the cancer grow. (Think about testosterone as a hormone that "feeds" prostate cancer cells.) Up to a point, the more testosterone the cancer cells have, the more the cancer can grow – and eventually spread (metastasize) to other parts of the body. Hormone therapy is designed to prevent testosterone from fueling the growth of these cancer cells.

Hormone therapy options

Orchiectomy – surgical removal of the testicles

Once a common treatment, orchiectomy is rarely used now, thanks to the development of advanced ADT drugs. The procedure removes the testicles – the source of most testosterone production. The scrotal sac is left intact, and patients can have testicular prostheses (artificial testes) implanted for cosmetic purposes. Orchiectomy is effective in drastically reducing levels of testosterone, but it has several downsides. Removal of the testicles is permanent and irreversible. Loss of the testicles makes it challenging to have intermittent hormone therapy, an advantageous treatment. And there is a psychological effect: Many patients feel distress related to the idea of lost masculinity if they undergo this procedure.

LHRH drugs

Luteinizing hormone-releasing hormone (also known as gonadotropin-releasing hormone, or GnRH) is a hormone that initiates production of testosterone. We have two types of drugs that act in different ways on LHRH to stop testosterone production:

• LHRH agonists (or GnRH agonists) work in a counterintuitive way. They prompt a continuous message from the brain to increase testosterone production. The testicles eventually respond to being overworked by switching off. Because of the initial overstimulation, some patients experience an increase in their testosterone level before it declines. This is also why patients starting LHRH therapy are also prescribed an antiandrogen drug, such as bicalutamide or flutamide, that decreases the cancer cells' ability to use testosterone.
• LHRH antagonists are newer drugs that can block LHRH without causing an initial testosterone flare. Consequently, antiandrogens may not be necessary.

Treatment with either type of LHRH drug is sometimes called medical or chemical castration. However, when the drug is stopped, the testicles usually resume producing testosterone. How much time this takes varies, ranging from several months in younger patients to several years or never in older patients. But, in general, the length of time for testosterone production to resume relates to the length of time on ADT.

All the LHRH drugs listed in the table below stop testicular testosterone production. They are all considered equally effective. The choice of which to use is usually based on cost, convenience or both.

LHRH medications
Generic name	Trade name	How is the drug given?	How much is given and how often?
Leuprolide acetate	Lupron	Injected into the muscle of the buttock	7.5 mg monthly or 22.5 mg every 3 months or 30 mg every 4 months or 45 mg every 6 months
Goserelin acetate	Zoladex	Injected beneath the skin of the abdomen	3.6 mg monthly or 10.8 mg every 3 months
Leuprolide acetate	Eligard	Injected beneath the skin of the abdomen	7.5 mg monthly or 22.5 mg every 3 months or 30 mg every 4 months or 45 mg every 6 months
Leuprolide acetate	Viadur	Surgically implanted into the upper inner arm	65 mg annually
Triptorelin pamoate	Trelstar	Injected into the muscle of the buttock	3.75 mg monthly or 11.25 mg every 3 months or 22.5 mg every 6 months
Degarelix acetate	Firmagon	Injected beneath the skin of the abdomen (This drug is an LHRH antagonist, does not cause a spike, and does not require an initial course of antiandrogens.)	240 mg initially (loading dose) followed by 80 mg monthly
Relugolix	Orgovyx	Oral	360 mg on first day (loading dose) followed by 120 mg daily

Antiandrogen medications

Antiandrogens (see table below) are medications that work by preventing cancer cells from using testosterone or its component dihydrotestosterone (DHT) – or work in both ways. There are a number of antiandrogen drugs, each with a slightly different mechanism. They don't stop the testicles or adrenal glands from making testosterone; rather, they inhibit the cancer cells' ability to use testosterone. The number of antiandrogens has increased recently, providing doctors and patients with more choices. An antiandrogen may be used in combination with an LHRH drug. This therapy is called combined androgen blockade (CAB) and is sometimes more effective than a LHRH agonist or antagonist alone.

Antiandrogen drugs
Generic name	Trade name	How is the drug given?	How much is given and how often?
Flutamide	Eulexin	Oral pills	250 mg three times daily
Bicalutamide	Casodex	Oral pills	50-150 mg daily, depending on situation
Nilutamide	Nilandron	Oral pills	150 mg daily

Androgen signaling inhibitors (see table below) make up a newer class of drugs that are used in combination with LHRH medications. These drugs are usually considered for patients with more advanced disease, as when the cancer has spread beyond the prostate gland. Each has particular side effects that require regular monitoring with simple blood tests. Additionally, some of these drugs may interact with other commonly prescribed medications, making it especially important for patients to have their doctor review all of their current medications and make any necessary changes prior to starting an androgen signaling inhibitor.

Androgen signaling inhibitors
Generic name	Trade name	Treatment dose	How it works
Abiraterone acetate and prednisone	Zytiga	Abiraterone (1000 mg daily) prednisone (5 mg or 10 mg daily)	Blocks androgen production by the adrenal glands
Enzalutamide	Xtandi	160 mg daily	Androgen receptor blocker
Apalutamide	Erleada	240 mg daily	Androgen receptor blocker
Darolutamide	Nubeqa	600 mg twice daily	Androgen receptor blocker

Intermittent hormone therapy

Hormone therapy can be given without interruption, but some patients are eligible for an approach known as intermittent hormone therapy, in which they cycle on and off ADT. Intermittent hormone therapy is the standard of care for patients with recurrence that is not metastatic. But it isn't right for all situations and must be discussed with your doctor.

Intermittent therapy can improve quality of life: You get a break from the therapy's adverse effects during "holidays," when testosterone levels are permitted to rise. Unfortunately, the drugs eventually lose their effectiveness in most patients with recurrent disease. When HT is started, most of the cancer cells are hormone sensitive, and depriving them of testosterone impairs their growth. At some point, the cells become ADT-resistant and find a way to either grow without testosterone or to produce their own. This shift can occur in a few months, in a few years, or never.

At UCSF, we generally prescribe intermittent therapy this way: You take the drugs until your PSA falls to its lowest point, then continue treatment another nine to 12 months. The drugs are then stopped, and your PSA is carefully monitored, typically with testing every one to three months. When your PSA rises to a level predetermined by you and your oncologist, you resume ADT for another nine to 12 months, at which point you can take another drug holiday. The PSA is again allowed to rise to a predetermined level, and the cycle continues.

Side effects of hormone therapy

Most side effects experienced by patients receiving HT are caused by low testosterone. The three most reported side effects are fatigue, hot flashes and sexual changes, including decreased libido and reduced erectile function.

Many of these side effects develop over time. Patients treated for eight months or less time are less likely to experience many of them, although some, such as hot flashes and sexual side effects, usually manifest within the first four to six weeks. Most of these side effects are reversible, diminishing or disappearing when the therapy is stopped and testosterone levels recover.

Not all patients experience all side effects, and there is much variability in their severity.

Here are the side effects patients most often report, along with suggestions for minimizing them:

• Hot flashes. How patients experience hot flashes varies greatly in frequency, intensity and duration. They are often the first side effect to arise, and most patients find them less bothersome over time. Recommendations: Troublesome hot flashes may be treated with medications, such as Effexor (venlafaxine) or Megace (megestrol). Avoid warm environments and spicy foods; both can trigger hot flashes. Some evidence suggests that acupuncture may help. Decreasing intake of alcohol and caffeine may help.
• Decreased libido. The majority of patients on ADT experience some decrease in sexual desire and some degree of erectile dysfunction.
  Recommendations: Working cooperatively with your partner to accommodate the changes resulting from HT can help you remain sexually active. Counseling for both partners is usually available.
• Mood changes. Low testosterone impacts brain chemistry and may result in depression, anxiety, irritability and other mood changes.
  Recommendations: Depending on the severity of these changes, antidepressant and antianxiety medications may be appropriately prescribed. They work differently for each person, so you may need to try a few to find one that works well for you. Exercise also can help. It is known to stimulate the brain to produce some of the enzymes that may be lacking. Seek out counseling and support groups, both of which can be helpful, and ask those around you to be tolerant.
• Fatigue. Low testosterone levels can cause fatigue directly or indirectly as a result of anemia (a reduction in red blood cells). Loss of muscle mass and mood changes can also contribute to fatigue.
  Recommendation: Participate in regular physical activity. Exercise is useful not only in dealing with side effects but in minimizing weight gain and reducing heart disease risk. Just walking for 30 minutes three times a week can provide some benefits.
• Muscle mass loss, weight gain or both. Loss of testosterone slows metabolism and interferes with muscle maintenance. Weight gain often shows in the belly.
  Recommendations: Participate in regular physical activity. Your exercise regimen should include weight training. If you're a UCSF patient, you can make an appointment with an exercise counselor who specializes in working with cancer patients.
• Breast enlargement (gynecomastia). This is caused by a hormonal imbalance in which estrogen, the female sex hormone, takes on a more dominant role. It may be accompanied by nipple tenderness or sensitivity. It occurs more commonly with antiandrogen drugs than with the LHRH medications.
  Recommendations: If the prospect of this side effect is upsetting, a single dose of radiation to the breasts at the start of treatment can be preventive. A medication called tamoxifen that blocks estrogen activity can also help to prevent this symptom.
• Increased appetite. Many patients find their appetite increases as their testosterone levels decline. This often leads to weight gain.
  Recommendations: Exercise boosts metabolism. A diet that promotes heart and prostate health is also helpful.
• Diminished brain function. Data about the effects of hormone therapy on brain function have been inconclusive, but many patients report changes in concentration, memory and clarity of thought. UCSF oncologists are developing a series of studies in conjunction with the UCSF Memory and Aging Center to evaluate the extent and timing of these side effects as well as the risk factors.
  Recommendations: Keep your brain active during treatment. This may include working; playing an instrument; or playing word, card or other types of games. Memory aides include making lists, writing reminders and setting alarm reminders.
• Hair loss or gain. Loss of testosterone results in loss of body hair over time. Patients on short-term hormone therapy may see little difference, but long-term treatment may lead to less hair on arms, legs, underarms and the genital area; facial hair may grow more slowly, too. Conversely, hair on the scalp may become thicker.
  Recommendation: Understand that growth restarts as testosterone levels rebuild.
• Genital shrinkage. Some patients experience shrinkage of the penis or testicles (hypogonadism) because of reduced testosterone.
  Recommendation: If this distresses you or your partner, discuss it with your doctor and consider counseling.
• Bone loss or osteoporosis. Older patients, smokers and patients on HT for more than 12 months are at a higher risk for developing osteoporosis, or thinning of the bones. The condition is diagnosed through a bone density test. If you expect to be on HT longer than 12 months, consult your doctor before starting therapy about having this imaging test to establish your baseline bone mineral density. A follow-up test should be performed every two years if previously normal and yearly if abnormal.
  Recommendations: Medications called bisphosphonates can effectively treat osteoporosis when bone density is significantly reduced. An oral medication, such as Fosamax (alendronate), is taken once a week, while infusions, such as Zometa (zoledronic acid), are given every three to four weeks or at longer intervals. Xgeva or Prolia (denosumab) is injected subcutaneously (under the skin); it is less harmful to kidneys than zoledronic acid but has other side effects. If you're prescribed zoledronic acid or denosumab, you'll also be on calcium and vitamin D supplements. Periodic blood tests to monitor calcium, phosphate and (for Zometa) kidney function will be part of your treatment plan. It's also important to have regular dental evaluations, both prior to and while on bone-targeted therapy.
  Your vitamin D level may be checked, and if it's low, your doctor may recommend supplements. Regular weight-bearing exercise is recommended. In particular, weight resistance training should be performed three times weekly.
• Anemia. While generally mild, a reduction in red blood cells may result from long-term hormone therapy (it's unlikely to occur within the first 12 months). This can contribute to fatigue.
  Recommendation: A blood test to evaluate iron levels can show whether iron deficiency is a factor.
• Abnormal liver function. In less than 5% of patients, oral antiandrogens irritate the liver, resulting in abnormal results in blood tests that measure liver function. When this occurs, it typically happens early in the use of antiandrogens, yet it can also occur after years of use with no noticeable side effects. Blood tests evaluating liver function should be done after the first month of therapy and every three months thereafter. These blood test abnormalities are usually detected long before symptoms appear. Discontinuation of the medicine almost always normalizes liver function. Switching to another antiandrogen often works as well.
  Recommendations: Ask your doctor to order liver function tests every three months. If your results are abnormal, you may be counseled to reduce your alcohol or acetaminophen (Tylenol) intake or make other modifications. Be sure your doctor knows about all the medications you take.
• Cardiovascular disease. Although some analyses have indicated that HT may slightly increase the risk of heart attack and stroke, this finding remains controversial. The risk appears to be highest for those who already have other risk factors, such as high blood pressure, high bloodstream cholesterol or diabetes mellitus.
  Recommendations: If you're at high risk for heart disease, be sure to discuss this with your doctor before starting hormone therapy. You should know your cholesterol and blood pressure levels and inform your primary care provider that you're on HT. Many drugs can help control cholesterol. Lifestyle changes in nutrition and exercise are important, too.
• Diabetes mellitus. Lack of testosterone is known to increase blood sugar levels. If you're diabetic, being on HT may require adjustments in how you manage your disease. If you're not diabetic, your blood sugar levels may increase.
  Recommendations: If you're diabetic, be sure to consult your primary care provider or specialist about whether you need to adjust your management plan. If you're not diabetic, your blood sugar levels will be checked periodically. In general, regular exercise and a healthy, fiber-rich diet help control blood sugar levels.
• Erectile dysfunction (ED). Hormone therapy reduces libido and impairs erectile function.
  Recommendations: ED drugs, such as Viagra, Cialis and Levitra, don't usually work well while patients are on hormone therapy. Other solutions, such as penile injections, penis pumps and penile prostheses, may be appropriate. Talk to your doctor about your options.
  A local prostate cancer support group can provide information and psychological support for addressing HT's side effects. Organizations that will help you find a group include Zerocancer, the American Cancer Society and the California Prostate Cancer Coalition. Also, for UCSF patients, the Patient and Family Support Center is available.

Diet and exercise

As previously mentioned, diet and exercise play important roles for people dealing with prostate cancer in general and with hormone therapy in particular. In terms of HT, a healthy diet and regular exercise may have these benefits:

• Slow cancer progression, as indicated in some studies relating particularly to exercise
• Reduce the impact that side effects have on both body and mind
• Diminish the potential harm of comorbidities (other medical conditions) by improving the body's general condition

UCSF resources

We provide valuable resources to support you through treatment and guide you in adopting a more healthful lifestyle.

The Ida & Joseph Friend Patient and Family Cancer Support Center at Mount Zion, located on the lobby level at 1600 Divisadero, and the Patient and Family Cancer Support Center at Mission Bay offer programs and lectures (such as "Nutrition and Prostate Cancer"), as well as comfortable places to sit if waiting for treatment. You can explore an excellent library and a selection of pamphlets from the UCSF "Health Matters" series. To stay informed, sign up for the monthly email newsletter. Find more information online or call (415) 885-3693.

Two programs are particularly worth singling out. As a UCSF patient, you can receive a free one-on-one nutrition counseling session. Ask your doctor about making an appointment with a UCSF dietitian. You can also see an exercise counselor, who will assess your current capacity for physical activity, formulate a practical program, direct you to classes, and follow up on your progress. Call (415) 514-6430 to make an appointment.

The UCSF Symptom Management Service is available for help with handling many of the side effects of hormone therapy. It includes programs to assist with managing pain, stress and other issues. Ask your doctor for a referral.