Treating Prostate Cancer

The treatment options for prostate cancer vary according to the stage of the cancer and include watchful waiting, radical prostatectomy, radiation therapy, and hormone treatment. Radiation therapy can be delivered from an external source (external beam radiation therapy) or by implantation of radioactive seeds (brachytherapy). Cryotherapy (freezing the prostate) is also used to treat prostate cancer.

Radical prostatectomy and radiation therapy can potentially cure prostate cancer when the disease is detected in its early stages. Hormone therapy is not curative and is generally used to slow the progression of the disease once it has spread to other sites. Though chemotherapy is effective in treating some types of cancer, it has been less successful for prostate cancer.

Because prostate cancer progresses more slowly than other types of cancer, men can take some time to carefully consider the various treatment options. They should talk to their doctor about the relative risks and benefits of each treatment and consider consulting physicians from different fields (urologists, radiation oncologists, and medical oncologists) to get a broader spectrum of opinions. Making a treatment decision is most difficult for men with early-stage prostate cancer, since more treatment options are available.

This section includes information on:

• Staging systems
• Watchful waiting
• External beam radiation therapy
• Brachytherapy
• Hormone therapy
• Cryotherapy
• Radical prostatectomy

Staging systems

After determining the extent of the cancer, doctors use one of two methods to describe the cancer's clinical stage. These are the Whitmore-Jewett and TNM (tumor, node, metastasis) systems.

The Whitmore-Jewett system uses stages A, B, C, and D—with A indicating the earliest cancer and D the most advanced—to describe the extent of the tumor. The stage is further subdivided with numbers, for example, stage A1 or A2, for a more specific indication of the percentage of cancerous tissue.

The TNM system assigns a T number (T1 to T4) to a tumor according to its extent on a digital rectal examination; an N number (N0 to N3) indicating lymph node involvement; and an M number (M0 to M1) to indicate the presence of distant metastases. These stages are further subdivided into a, b, and c to describe how the cancer was diagnosed and the extent of cancerous tissue. The most commonly diagnosed stage of cancer today is T1c, indicating that the cancer was not found during a digital rectal exam but was identified by needle biopsy after finding an elevated PSA.

Watchful waiting

Watchful waiting involves no immediate treatment but does involve close monitoring for cancer progression. This treatment approach is most often recommended for men who are unlikely to live long enough to benefit from treatment and for those who have disease that is too far advanced to cure. In addition, some men who are thought to have small prostate cancers that are likely to grow very slowly may opt for this approach.

Men who choose watchful waiting must see their doctor regularly to determine whether the cancer is progressing. If the cancer progresses, treatment options such as radical prostatectomy or radiation therapy may be considered, particularly in younger men. Recommendation on the frequency of visits and the tests conducted at each visit varies from doctor to doctor. Between appointments, men of any age should call their doctor if they experience blood in the urine, difficulty urinating, or new onset of pain.

External beam radiation therapy

External beam radiation therapy (EBRT) involves aiming beams of radiation at the tumor from outside the body. It is a treatment option for men with localized prostate cancer (stage T2) or locally advanced disease (stage T3). Although no randomized trial has directly compared radical prostatectomy with radiation, available evidence suggests that, for patients with cancer confined to the prostate, either approach is associated with a good chance of being cancer free five to 10 years after treatment.

External beam radiation therapy is also used as a palliative treatment (a treatment aimed at relieving pain and limiting disease complications, rather than curing a disease). For a patient with prostate cancer that has spread to the bones, radiation therapy can reduce pain and lessen the likelihood of bone fractures. It can also be used to treat neurological symptoms resulting from compression of the spinal cord if cancer has spread to the spine.

Complications of radiation therapy mostly involve adverse effects on the urinary tract and bowel, and usually disappear days to weeks after completing treatment. The risk of long-term urinary complications, such as blood in the urine, bladder problems, or narrowing of the urethra, is about 8 percent. The risk of long-term rectal complications, such as bleeding, ulceration, rectal inflammation, narrowing of the rectum, or chronic diarrhea, is about 3 percent. The risk of erectile dysfunction becomes more likely with time. In one recent study of 434 men, 86 percent were potent 15 months after treatment but only 50 percent were potent six years later. Younger men and those with normal sexual function before radiation therapy are the most likely to maintain potency.

This section also includes information on advanced alternatives to standard EBRT.

Advanced techniques

The standard external delivery method is called external beam radiation therapy (EBRT), in which beams of radiation are aimed at the tumor from outside the body. Because radiation to the prostate can damage the nearby rectum, bowel, and bladder, researchers have refined and developed alternatives to standard EBRT. Three-dimensional conformal radiation therapy (3DCRT) is the most popular refinement; intensity-modulated radiation therapy (IMRT) is a further refinement. The newest technique is proton beam radiation.

• 3DCRT: In 3DCRT, the radiation oncologist uses dozens of computed tomography (CT) scans to "conform" the radiation beams to the precise shape of the tumor. Custom shaping of the beams permits higher dosing of radiation to the tumor while avoiding healthy tissue and nearby organs.
• IMRT: A further refinement of 3DCRT is intensity-modulated radiation therapy (IMRT), in which the intensity of each beam is raised or lowered to meet the needs of the patient. Unlike 3DCRT, in which the radiation oncologist must arrange the beams by hand and determine the total dose of radiation to give, IMRT software determines the number, orientation, and intensity of the beams.
• Proton beam radiation therapy: This employs the specialized targeting of 3DCRT, but it uses proton beams instead of X-rays. Protons, which are positively charged subatomic particles, are effective at killing cells at the end of their path while causing minimal damage to the tissues they pass through. The theory is that these particles can allow for higher radiation doses with fewer side effects.

Brachytherapy

Another method of treating prostate cancer with radiation is brachytherapy, in which radioactive seeds (tiny metal pellets) are implanted directly into the tumor. Brachytherapy is appropriate for men with early-stage prostate cancer (stage T1) who have a Gleason score of 6 or less and a PSA level less than 10 ng/mL. But the procedure does not appear to be as effective as radical prostatectomy or external beam radiation therapy for men with higher stages or grades of disease.

The side effects of brachytherapy are similar to those of external beam radiation therapy—urinary and bowel problems. But these complications may occur more often with brachytherapy than with external beam radiation. In addition, the radioactive seeds can migrate to other parts of the body, such as the lungs, though research suggests that seed migration has no negative consequences.

Because brachytherapy is associated with a lower chance of a cure and a somewhat higher chance of complications than external beam radiation therapy, the latter is still considered the gold standard of radiation treatment for prostate cancer.

This section also includes information on advanced techniques for brachytherapy.

Advanced techniques

Brachytherapy, also known as seed therapy, is a common method of internal radiation and is considered an option for men who choose radiation therapy. The two main refinements of brachytherapy are MRI-guided brachytherapy and high-dose-rate brachytherapy.

• MRI-guided brachytherapy: In a further refinement of the process, a technique using magnetic resonance imaging (MRI) to guide seed implantation has been developed. An MRI allows for a much more precise placement of the seeds than ultrasound, according to its developer. MRI-guided brachytherapy is not widely available because few oncologists have access to the necessary equipment.
• High-dose-rate brachytherapy: Another refinement to the brachytherapy procedure is high-dose-rate brachytherapy, in which the seeds are inserted into the prostate temporarily, rather than permanently. Ultrasound is used to guide the placement of approximately 25 tiny hollow plastic needles into the prostate. While the patient remains in the hospital, a single radioactive pellet is delivered through each needle several times over a 24- to 48-hour period. After each treatment, the pellet is removed. After the final treatment, the needles are removed as well and the patient is discharged.

Hormone therapy

The discovery that male sex hormones (androgens), testosterone in particular, are required to maintain the size and function of the prostate led to the developments of treatments designed to interfere with these effects of testosterone. Preventing testosterone from acting on prostate cancer cells can temporarily cause the cancer to regress, or to least to grow more slowly. However, because some prostate cancer cells are able to grow without testosterone (they are called androgen-independent or androgen-insensitive cells), the tumor will continue to grow despite the withdrawal of this hormone. Thus, hormone therapy is useful for the treatment of prostate cancer but does not offer a cure.

Hormone therapy used to be reserved for men whose prostate cancer had spread to other tissues (such as the lymph nodes or the bones) and could not be completely eradicated by surgery or radiation. Now, hormone therapy also can be used to treat men whose disease has not spread but is expected to. Because all effective forms of hormone therapy produce erectile dysfunction and loss of libido (sex drive)—and none is curative regardless of when treatment begins—an earlier start may not be worth the risks of these and other side effects (such as hot flashes or loss of energy) or the costs of hormone therapy. However, the short-term use of hormone therapy in men with early-stage prostate cancer—particularly in combination with surgery or radiation therapy—has grown in popularity.

The most significant side effects of hormone therapy are erectile dysfunction in about 90 percent of patients and loss of libido. Other side effects include breast enlargement, weight gain, loss of muscle mass, osteoporosis (decreased bone mass), and fatigue. About two thirds of men have hot flashes—like those experienced by women during menopause. Hot flashes are not harmful. Hormone therapy does not cause the voice to change in pitch, as some men fear.

There are two approaches to hormone therapy, also called testosterone withdrawal, androgen blockade, or castration. The first is surgical removal of the testicles, which produce about 95 percent of the body's testosterone (surgical castration). The second is the use of medications that interfere with the manufacture or actions of testosterone (medical castration). These medications include estrogens, luteinizing hormone-releasing hormone (LH-RH) analogs, gonadotropin-releasing hormone antagonists, and antiandrogens.

This section includes further information on:

• Antiandrogens
• Total androgen blockade
• Estrogen preparations
• Gonadotropin-releasing hormone antagonists
• Intermittent androgen suppression
• LH-RH analogs
• Other medications
• PC-SPES
• Surgical castration

Antiandrogens

To stimulate prostate cells (both cancerous and noncancerous), testosterone must first bind to specific androgen receptors within the cells. Drugs called antiandrogens can bind to these receptors and prevent testosterone from stimulating the cells. Since antiandrogens do not block testosterone production—which sets them apart from other types of hormone therapy—their use may preserve erectile function in some patients. Three antiandrogens are approved by the FDA for the treatment of advanced prostate cancer: bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron).

When used alone, antiandrogens may not be as effective as other forms of castration. In addition, antiandrogens can cause hot flashes, breast enlargement, diarrhea, and, in rare instances, liver damage. To monitor for liver damage, men taking an antiandrogen must have their liver function tested a few months after starting treatment. Signs of liver problems include nausea, vomiting, fatigue, and jaundice. Nilutamide may slow the ability of the eyes to adapt to darkness. This side effect lasts for about four to six weeks.

In 40 percent to 75 percent of men taking an antiandrogen, an increase in PSA levels occurs, indicating disease progression. But if the medication is discontinued, PSA levels will fall. Why this occurs is not clear. It is possible that a mutation in the cancer cells results in their response to stimulation by antiandrogens.

Total androgen blockade

Since the adrenal glands also produce small amounts of androgens, including testosterone, some doctors use antiandrogens in combination with surgical or medical castration to block the possible effect of adrenal androgens on prostate cells. The combination of an antiandrogen (to block the effect of adrenal androgens) and surgical castration, an LH-RH analog, or a gonadotropin-releasing hormone antagonist (to halt production of testicular androgens) is referred to as total androgen blockade or total androgen suppression. Despite promising preliminary findings, numerous studies have failed to demonstrate that total androgen blockade prolongs life more than simply halting the production of testicular androgens alone.

Estrogen preparations

A synthetic form of the female hormone estrogen can lower testosterone levels to the castrate range by blocking the release of luteinizing hormone from the pituitary gland, thereby shutting down the production of testosterone. Daily doses of synthetic estrogen (Premarin) are as effective as surgical castration, though the hormone takes longer to work; testosterone levels fall over a two-week period.

The most significant side effect of synthetic estrogen is an increased risk of cardiovascular complications. These include heart attack, stroke, blood clots in the lungs or legs, phlebitis (inflammation of the veins) and edema (swelling of the legs). Because of these risks, people with a history of heart disease or thrombophlebitis (vein inflammation due to a blood clot) should not use estrogen therapy. In other people, these side effects can be minimized by using low doses of estrogen. In addition, taking an aspirin every other day helps to lower the risk of heart attach and blood clots; edema can be treated with diuretics (drugs that promote water loss through urine). Estrogen can also cause nausea and vomiting. And, like surgical castration, estrogen can cause breast enlargement and erectile dysfunction.

With the approval of LH-RH analogs, estrogens are no longer widely used. However, there is renewed interest in diethylstilbestrol (DES), a form of estrogen used in the 1960s for advanced prostate cancer. In addition, researchers are investigating the potential of an estrogen patch to lower testosterone levels without the side effects associated with other types of hormone therapy.

Gonadotropin-releasing hormone antagonists

In 2003, the FDA approved abarelix (Plenaxis) for the treatment of advanced prostate cancer that does not respond to other hormone therapies. Abarelix works by lowering levels of testosterone in the blood. It is equivalent to treatment by surgical castration in delaying progression of cancer initially, but effectiveness decreases over time. The drug is given by injection every two weeks for the first month, then every four weeks. Because it can cause life-threatening allergic reactions in some men, the drug is available only through doctors participating in a risk management program. Side effects include hot flashes, sleep disturbance, breast enlargement, and dizziness.

Intermittent androgen suppression

In this approach, androgen blockade is achieved chemically (using an LH-RH analog or gonadotropin-releasing hormone antagonist alone or in combination with an antiandrogen) until PSA levels fall to the castrate range. Treatment is then discontinued until PSA begins to climb again. The rationale for this approach is the belief that hormone therapy encourages the growth of androgen-insensitive cancer cells (the cells that cause the tumor to grow despite hormone therapy). Some doctors believe that cycling therapy on and off may delay the emergence of these deadly cells. In addition, intermittent androgen suppression is associated with fewer side effects, since men discontinue therapy for periods of time.

More studies are needed to determine whether intermittent androgen suppression is as effective at slowing disease progression as continuous androgen support. But many oncologists use this approach routinely.

LH-RH analogs

These are synthetic products with chemical structures almost identical to natural LH-RH. Initially, they behave like LH-RH and stimulate the release of luteinizing hormone from the pituitary gland, causing an increase in testosterone production. But after a short period, they block the release of luteinizing hormone and reduce testosterone secretion from the testicles. The result is testosterone levels similar to those that occur after surgical castration or with estrogen. LH-RH analogs are equivalent to surgical castration and estrogen in their ability to delay progression of cancer and prolong survival.

Commonly used LH-RH analogs are goserelin (Zoladex), leuprolide (Eligard, Lupron), and triptorelin (Trelstar). LH-RH analogs are traditionally given as injections every month or every three months. Another option is an implanted drug delivery system (Viadur) that reduces leuprolide continuously for one year.

The initial increase in testosterone with LH-RH analogs may be severe enough to exacerbate bone pain in men with prostate cancer that has spread to the bones and can be prevented with an antiandrogen until testosterone levels fall to the castrate range about two to three weeks later. Other side effects of the LH-RH analogs include erectile dysfunction, loss of libido, hot flashes, weight gain, fatigue, and decreased bone and muscle mass. In addition, some men experience irritation at the injection sites. LH-RH analogs are less likely than estrogen to cause breast enlargement, nausea, vomiting, and cardiovascular problems.

Other options

Testosterone levels can be reduced within 24 hours with ketoconazole (Nizoral)—a drug approved by the FDA to treat fungal infections that also inhibits the synthesis of adrenal and testicular androgens. Ketoconazole is used only when lowering androgens rapidly might be beneficial (for example, to alleviate pain). It is used only in the short term, because it raises luteinizing hormone levels, which can cause testosterone levels to rise and disease progression to occur. Ketoconazole can also cause liver problems.

Flutamide in combination with finasteride has been studied as a treatment option for advanced prostate cancer. Researchers hoped this combination would be effective, since finasteride lowers levels of dihydrotestosterone and could potentially enhance the ability of flutamide to block androgen action. But this approach is less effective than standard hormone therapy using an LH-RH analog or surgical castration.

PC-SPES

PC-SPES was an over-the-counter product marketed as an herbal remedy for prostate cancer in the United States. It was removed from the market in 2002 after the discovery that the product contained several prescription drugs: the synthetic estrogen DES, the potent anti-inflammatory drug indomethacin (Indocin), and the blood thinner warfarin (Coumadin). Men who had good results with PC-SPES should ask their doctors about taking DES.

Surgical castration

Surgical removal of the testicles, known as bilateral orchiectomy, is the easiest and oldest way to interrupt the effect of testosterone on prostate cancer cells. The operation can be performed in about 20 minutes under spinal or local anesthesia, and the patient can usually go home the same day. People on anticoagulant therapy may not be candidates for surgical castration, since they are at risk for uncontrolled bleeding.

Surgical castration involves making a small incision in the scrotum and removing each testicle. Neither the operation nor the recovery is painful. In a variation of this procedure, called a subcapsular orchiectomy, only the contents of the testicles are removed. The empty shell of each testicle is left in place, resulting in a more satisfactory outward appearance. However, some surgeons do not use this technique because there is a risk that some testosterone-producing cells may be left behind. The effect of orchiectomy is almost immediate. Within 12 hours of the procedure, testosterone levels fall to what is known as the castrate range. Because it is so effective, orchiectomy is the standard to which all other hormone therapies are compared.

Even though it is the most effective and least expensive form of hormone therapy, only about a quarter of men choose surgical castration. Obviously, psychological issues influence the decision to have this operation, which cannot be reversed. Men who are psychologically troubled by orchiectomy may prefer medical castration. Medical treatments can be as effective as orchiectomy, and the side effects are similar. Despite these side effects, hormone therapy—whether surgical or medical—prolongs the life of most men.

Cryotherapy

Cryotherapy is accomplished by placing a probe through the perineum and into the prostate. The probe is attached to a source of nitrogen or argon, which cools the tip of the probe to extremely low temperatures. The low temperature freezes and destroys the prostate cancer cells. Although cryotherapy is a minimally invasive procedure, the long-term effectiveness of this technique is not well known and the risk of side effects such as erectile dysfunction is high. As a result, enthusiasm for cryotherapy as an initial treatment has diminished. Men in whom radiation fails to eradicate disease locally are sometimes treated with cryotherapy.

Radical prostatectomy

Radical prostatectomy (surgical removal of the prostate) offers the possibility of a cure only if the cancer has not spread to the lymph nodes in the pelvis or to other parts of the body. Therefore, when the risk of spread is judged to be high, some surgeons perform a laparoscopic biopsy to obtain samples of the lymph nodes before the planned prostatectomy; others sample the lymph nodes at the time of the scheduled prostatectomy and discontinue the operation if the cancer has spread. However, it is uncommon today (because of PSA testing) to find disease that has spread to the lymph nodes at the time of surgery. If enlarged lymph nodes are discovered on a CT scan or MRI, a fine needle biopsy to remove some cells from the lymph nodes may be performed to determine whether the cancer has spread.

Radical prostatectomy is the only treatment for localized prostate cancer (cancer confined to the prostate) that has been proven to reduce deaths from the disease. A study published in 2002 found that Swedish men randomized to radical prostatectomy had a 50 percent reduction in their risk of dying of prostate cancer eight years after diagnosis, compared with men randomized to watchful waiting.

Rare complications of radical prostatectomy include narrowing of the urethra (urethral stricture), damage to the rectum, and the surgical and anesthetic risks (including death) that accompany any operation.

Some surgeons are using laparoscopy to perform radical prostatectomy. The laparoscopic procedure is less invasive than traditional prostatectomy; it requires five tiny incisions on the abdomen rather than one long one. It is still considered an evolving procedure, however.

This section includes information on:

• Nerve-sparing technique
• After surgery

Nerve-sparing technique

The anatomical, or "nerve-sparing," technique has reduced the risk of severe incontinence to 1 percent to 3 percent and the chance of mild incontinence to around 10 percent. The risk of erectile dysfunction varies with the age of the man and the skill of the surgeon. One group of researchers reported successful recovery of erections in 68 percent of men treated with nerve-sparing surgery. Full recovery of erectile function can take more than a year in some cases, however. When erectile dysfunction does occur after surgery, it can usually be treated successfully.

In the nerve-sparing procedure, the tiny nerve bundles that sit on either side of the prostate and that are required for an erection are carefully dissected away from the prostate but are otherwise left intact. (If the cancer is suspected to have spread to these nerves, however, they will be removed.)

After surgery

After radical prostatectomy, PSA tests are used to evaluate the success of the surgery and to monitor for disease recurrence. An undetectable PSA level (usually less than 0.2 ng/mL) after radical prostatectomy indicates that all the prostate tissue (both benign and malignant) has been removed. A detectable PSA immediately after surgery means that the tumor had already spread to other tissues before the surgery and thus could not be totally removed. A subsequent rise in PSA levels indicates the cancer has recurred in the area of the prostate or in another place in the body.

For men with cancer confined to the prostate (stage T1 or T2) before treatment, the chance of a cancer recurrence—indicated by detectable PSA levels—10 years after treatment is around 30 percent. A detectable PSA indicates a cancer recurrence months to years before the cancer is visible by a CT or bone scan. When evidence indicates that residual cancer is limited to the pelvis, radiation therapy is a treatment option. A detectable PSA in the first year after treatment indicates a high probability that the disease has spread beyond the pelvis and that radiation will not successfully eradicate the cancer. In this case, hormone therapy is considered, particularly if the cancer has spread to the bones.