TREATMENT OF PROSTATE CANCER WITH HORMONE THERAPY

The prostate gland is uniquely male. Its very existence is due to the presence of male hormones, primarily testosterone, which the prostate, and most prostate cancers require to grow. This observation led urologists to the use of hormone reduction to treat prostate cancer in the 1940s and except for newer drugs, the principle of hormone reduction still stands today. Today the most common ways of effecting male hormone reduction are injections of medications which literally turn off the testicles.

In patients who have had spread of the cancer out of the prostate to other parts of the body such as lymph nodes, bone, lung, or liver, we often recommend hormone treatments. When spread of the cancer has occurred, the disease cannot usually be cured with surgical removal or with radiation treatments. This is because the cancer is almost always more widespread than we can diagnose and surgery or radiation would certainly fail to control enough of the cancer to be effective. Since hormone therapy treats the entire body, cancer cells too small to see can be treated, no matter where they are.

Occasionally, we treat patients with localized prostate cancer with hormones as well. In patients that for varied reasons cannot undergo surgery or radiation immediately, hormone treatment allows us to delay treatment. Another situation is when we want to shrink the prostate cancer to allow surgery or radiation to possibly be more effective.

ORCHIECTOMY (Removal of Testicles)
The testicles manufacture almost all of the male hormones. Therefore, removal of both testicles lowers the hormone levels sufficiently to often achieve an excellent response against the prostate cancer. The procedure requires a brief anesthetic (general, spinal or local) and usually requires less than 30 minutes to perform. In most instances, the patient goes home from the hospital on the same day. There is some discomfort that is usually treated with a mild pain medication and a few days of restricted activity. A small chance of infection exists, along with the risks associated with the anesthesia. Prosthetic implants, removed from the market at the time of the silicone breast implant scare, will be returned to the marketplace soon and can be placed, if so desired.

To date, there is no statistically significant difference in survival for patients treated with drugs compared to removal of the testicles.

Hormonal Injections (Viadur, Lupron or Zolodex)
These are long-acting injectable drugs (Lupron/leuprolide, Zolodex/goserlin) that act by turning off the testicles' ability to make male hormones. The action of the drug is actually on the hypothalamus and pituitary gland in the brain, which makes special hormones that stimulates the testicles to release testosterone. These drugs called 'LHRH or GHRH agonists' actually exhaust the pituitary of the releasing hormones. Kind of complicated, but in the end, the testicle does not make any significant amount of hormone, just as if they had been removed. The injections have no direct effect on the cancer, only an effect on the testicles' ability to make testosterone. The lack of male hormone circulating in the blood treats the prostate cancer. The major advantage is that there is no need for surgical removal of the testicles and the treatment is reversible if stopped. There are really no disadvantages other than the need for an injection every 1, 3, or 4 months, and the cost of the medication that may be as high as $600 per month. Usually, these medications are continued indefinitely. In almost all cases, one's insurance covers these costs. Allergic reactions can occur. Otherwise the shots are identical to the removal of the testicles.

A newer method of delivering the same medications (leuprolide) is now available using an implanted one-year pellet. The pellet or implant called 'Viadur' is a miniature pumplike device about the width of a pencil lead. It is loaded with one year of leuprolide and is placed just under the skin above the elbow crease using a local anesthetic. The implant can be changed every year to continue the medication. The implants have the distinct advantage of providing continuous therapy for the entire year without the need for repeated injections. For patients who travel, particularly in the winter months, the convenience of once-a-year dosing is obvious.

Another medication being tested, but not yet released for use by the FDA is a hormone injection (Abarelix) that directly blocks the action of the releasing hormone in the pituitary, called an 'LHRH or GHRH antagonist'. For the time, these drugs will require monthly injections and the cancer response results will be similar to available drugs. The advantages include a quicker onset of action (by a couple of weeks) Again, these are not available yet.

Female Hormones
Until the mid 1980s, female hormones in pill form, particularly Stilbesterol, were used to treat prostate cancer. Female hormones act on the male pituitary gland in the brain to reduce the release of a special pituitary hormone that stimulates the testicles to release testosterone. Female hormones had the advantage of requiring only a daily pill to take, but has the disadvantage of increased risks of heart attack and stroke and also caused painful breast enlargement in many men. Stilbestrol (or DES, as it is known) has been withdrawn from the market but other forms of female hormones still exist. These include TACE, Premarin, Estrace, and Estratab. Estradurin is a long acting injection that lasts two to four weeks. All of these drugs have been approved in the treatment of prostate cancer. Skin patches or 'transdermal estrogen' are also effective, but have not been approved for use in prostate cancer. To date, there is no statistically significant difference in survival for patients treated with female hormones compared to removal of the testicles or other drugs.

We still use female hormones to reduce the effects of hot flashes in some men, and occasionally in men whose tumors have started to grow again despite other types hormone treatments.

INTERMITTENT HORMONE THERAPY
We are currently investigating intermittent hormone therapy. Intermittent hormone therapy is a treatment regimen where hormone therapy is started and when the cancer shrinks to a certain level as measured by the PSA, we stop the hormone therapy. Treatment is re-started when the cancer grows again (as measured by PSA). The advantage of intermittent hormone therapy is a reduction in the side effects of the hormone therapy during the periods that the patient is off treatment and reduced overall costs. Early studies have suggested that success in treating the cancer is not hurt by using intermittent therapy. Intermittent therapy is still investigational. The amount of time one needs to be on treatment and the exact time to restart treatment if the cancer returns has not been established.

Additional Hormone Therapy
Many studies have suggested that the addition of another type of medicine called antiandrogens may help potentiate the effectiveness of either hormone injections or removal of the testicles. The most common antiandrogens used are called flutamide (Eulixen), bicalutamide (Casodex) or nilutamide (Nilandron). These drugs, which are similar in their action and taken in pill form, further reduce the hormone levels by blocking the action of remaining male hormones (mostly made in the adrenal glands). Controversy still exists as to the effectiveness of this additional treatment and the cost is about $300 per month, and many insurance companies including Medicare will not pay for them. A certain percentage of men will have some reaction to the medication, particularly diarrhea (more common in flutamide than bicalutamide or nilutamide) and breast enlargement (gynecomastia). The symptoms resolve in time or the dosage can be reduced. At this time, we suggest that flutamide, bicalutamide or nilutamide be used, IF the cost of the medicine will not be a burden and the side effects are minimal. Remember, its usefulness is still not a certainty to all investigators, so that if you do not use antiandrogens, you shouldn't feel that you are getting inferior or substandard treatment.

One recent study showed no benefit to the antiandrogen flutamide (Eulixen) when used in conjunction with orchiectomy (removal of testicles).

There is evidence both for and against using antiandrogens alone as the first therapy. Some European studies have shown high dose bicalutamide (Casodex)(three times the normal dose) is just as effective as hormonal injections or removal of the testicles. The major drawback of high dose antiandrogen is increased breast swelling and tenderness. Older studies using standard dose flutamide suggested that it is not as effective as hormonal injections or removal of the testicles. However adding Proscar 5-10 mgs daily to flutamide 125-250 mgs every 8 hours may be as effective as high dose Casodex or LHRH agonists.


The use of flutamide causes diarrhea in about one out of six patients. If the diarrhea is significant, flutamide is usually discontinued and then restarted at lower doses. As the body gets used to the flutamide, diarrhea does not seem to be as much a problem. If the flutamide cannot be tolerated, it is not used. A small percentage of men on flutamide will have temporary abnormalities of blood tests. Bicalutamide has a lesser incidence of diarrhea and needs to be taken only once a day. It costs about the same. Nilutamide has a lesser incidence of diarrhea, but a small percentage of patients can develop a type of pneumonia called interstitial pneumonitis. These side effects are almost always reversible as soon as the drug is discontinued.

A few physicians add a third drug called finasteride (Proscar) to increase the hormone blockade. Finasteride is a drug that is usually used for treating benign enlargement of the prostate or BPH (benign prostatic hyperplasia). It has almost no side effects. Its use for prostate cancer treatment is investigational.

Sequential Therapy
In an attempt to reduce some of the side effects of complete hormone reduction, some cancer specialists have suggested a slower step by step treatment regimen. When the treatment is no longer effective, a stronger medication is then used. Some physicians will initially try to use antiandrogens alone (flutamide or bicalutamide) or with finasteride but without major hormone reducing medications (Lupron or Zolodex). In some cases, the dosages of antiandrogen are raised. Initial response rates are similar to removal of the testicles in some studies. When this type of treatment failed, many men did respond to subsequent hormone reduction. The major benefit is the absence of hot flashes and the ability to continue to perform sexually in those men who were previously sexually active. Results are preliminary and this type of treatment for prostate cancer must be considered experimental at this time.

When is Hormone Therapy used?
Hormone therapy can be used in the following situations:

1. The cancer has spread to other areas of the body away from the prostate, such as bone, lung, liver, lymph nodes (otherwise known as metastases or metastatic cancer) or merely a rising PSA after surgical removal or radiation treatments to the prostate. The exact time to start treatment varies with each patient. In some patients treatment is started when the diagnosis of metastatic disease is made, in others, we may wait for symptoms, such as pain, before starting treatment. Overall survival time may be improved by starting hormone treatments earlier. This is particularly true for patients with higher grade cancers (Gleason score 8, 9 or 10) or more advanced disease. Some series of patients with very early spread of cancer can have very long survivals. In patients with advanced cancers, the survival benefits are less. The major advantages of delaying treatment are the lack of side effects from the hormone therapy and the reduced cost. Clearly, when patients have symptoms of advanced cancer or have some impending injury such as involvement of a weight bearing bone or blockage of the urinary tract, we always start therapy immediately.

2. As preparation for radical surgery or radiation therapy or implants to cure the cancer. Some studies have shown that hormone therapy can be used to make radical prostate surgery or radiation therapy more successful. The treated cancer shrinks before and during hormone therapy, thereby possibly increasing chances for successful curative therapy. The hormone therapy is stopped after surgery or radiation. This is investigational for now.

3. In many cancers, such as breast and testes, we use a technique called adjuvant therapy. Adjuvant therapy means that some treatment, usually chemotherapy but sometimes radiation therapy, is used to prevent recurrence of a cancer after surgical removal or radiation therapy (external or implant) of all known tumor. Some tumors, whether advanced in stage or grade of cancer, have a high chance of recurrence, even if all known tumor is removed. Some researchers are now considering the use of hormone (and radiation) treatments in selected patients with prostate cancer after radical prostatectomy. This treatment option is still experimental at this time and no long term data is available to tell us how effective adjuvant hormone therapy might be in prostate cancer.

How long is hormone therapy used?
For patients with metastatic cancer, the therapy is used indefinitely (continuous or intermittent) as long as the therapy is successful in controlling or stopping the growth of cancer.

As preparation for radical surgery or radiation therapy or seed implantation, the therapy is usually given for three to four months and perhaps as long as nine to twelve months. Surgery is then performed and the medication is stopped. In some radiation series, the hormones therapy has been continued for as long as three years.

Herbal Therapy
To date, no definite evidence exists to show that any dietary changes or herbal therapy will cure prostate cancer.

PC SPES, the most popular herbal remedy for prostate cancer, is a commercially available combination of eight different herbs and has been touted as a non-hormonal treatment for prostate cancer. The eight herbs are chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto and scutellaria (skullcap). Even though PC-SPES is promoted as a non-hormonal therapy for prostate cancer, it is obvious that many herbs do, in fact, have hormonal activity.
Recent studies clearly show that PC SPES is active against prostate cancer. Researcher have concluded that PC-SPES has significant female hormone (estrogenic) activity with a significant reduction in male hormone levels (tesosterone). All the patients studied had side effects associated with the use of female hormones, namely breast tenderness and loss of sex drive (libido) and impotence. 5 percent of men had a blood clot in leg with pulmonary embolus, a known and significant negative side effect of female hormone use in men.

In summary, PC-SPES does seem to have action against prostate cancer that is sensitive to a reduction in male hormone levels. The claim that PC-SPES is 'non-hormonal' is untrue, however, as all research points to a reduction in male hormone levels in men taking the drug. So far, we have no studies or information that PC-SPES adds or takes away from current hormone treatment of prostate cancer. In most likelihood it seems to add little to the current drug treatment protocols. Some reports of PC-SPES working in men who do not respond to hormones have been seen but additional studies need to be done to prove this.

Other herbal remedies include green tea, low fat diets, soy powder, selenium and Vitamin E, Lycopene, Essiac and Cat's Claw, Galactose, genistein, and AHCC (activated hexose correlated compound), Shark and bovine cartilage extracts. No herbal have been shown to be effective against prostate cancer and all come with the warning on the label that none of these drugs are to be used to treat any known disease!


SIDE EFFECTS OF HORMONE THERAPY
The most problematic are 'hot flashes'. Hot flashes, flushing or hot flushes are synonymous words for the episodes of sensation of increased warmth usually in the upper body and face. Technically hot flushes is the correct term, but hot flashes seems to be commonly used. Hot flashing occurs with a reddening of the skin and often with sweating. The episodes may last anywhere from seconds to many minutes, but usually last only two or three minutes. Most of the time the episodes occur without cause, but in some men can be triggered by changes in position, ingestion of hot fluids or changes in outside temperature. Hot flashes occur in two-thirds of the men who receive drugs which inhibit the production of male hormone, and at least 50% of the men who have undergone removal of the testicles. In many patients the incidence of hot flushes decrease over time, but unfortunately in some other patients the flushing continues unabated for years.

Most men will have little or no libido or sex drive and almost all men will be unable to obtain a satisfactory erection.

What are long-term risks of hormone therapy?
Osteoporosis, or 'thinning of bones', is a potential problem with some men whose male hormones are reduced for extended periods of time (years) and who have a tendency to have osteoporosis (thin men or family history of osteoporosis). Other factors for osteoporosis must be evaluated. This includes the use of steroids (cortisone or prednisone), immobility (inability to exercise), excessive use of alcohol, smoking, and prior history of fractures. These patients might need bone density studies after they have been on hormone therapy for more than three years. If osteoporosis is present, medical therapy may be needed to prevent fractures. This therapy may include weight bearing exercises, calcium and vitamin D supplements or the use of drugs to restore bone density such as Fosfamax.

Loss of stamina or fatigue may also occur. This varies tremendously between patients and unfortunately no therapy exists to combat this side effect.

HOW LONG WILL THE HORMONE THERAPY WORK?
Unfortunately, hormone therapy is effective only temporarily in many patients. Eight out of ten men will have an initial and dramatic reduction in size and control of their prostate cancer. However the response is rarely permanent. Often within 2-4 years after starting hormone treatment, cancers that have initially responded to hormone therapy will no longer respond and the cancer will start to grow again. This is called 'hormone refractory cancer' and may require different types of therapy.

Summary
Hormone treatments for prostate cancer have been used successfully for over 50 years. The overall success rate or chances of the cancer shrinking is greater than 70%. In those that respond, the length of time that the tumor remains under control is variable, but can be many, many years. We will continue to follow your cancer with examinations, blood tests (particularly PSA) and other scans, depending on your circumstances. Let us know if you have any questions or concerns and we'll try to answer them. You may also call the National Cancer Institute hot line at 1-800-4-CANCER..