Prostate Cancer

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Prostate Cancer

WHAT IS PROSTATE CANCER?

Prostate cancer is a malignant tumor that arises in the prostate gland. [ See Box The Prostate Gland, below. ] As with any cancer, if it is advanced or left untreated in early stages, it can eventually spread through the blood and lymph fluid to other organs. Fortunately, prostate cancer tends to be slow growing compared to other cancers. As many as 90% of all prostate cancers remain dormant and clinically unimportant for decades. This high incidence of latent or incidental malignancy is unique to the prostate gland. Most older men eventually develop at least microscopic evidence of prostate cancer, but it often grows so slowly that, as one specialist has written, many men with prostate cancer "die with it, rather than from it."

The Prostate Gland

Description of the Prostate Gland

The prostate gland is located between the bladder and the rectum and wraps around the urethra (the tube that carries urine through the penis). It is basically composed of three different cell types:

Smooth muscle cells, which contract during sex and squeeze the fluid from the glandular cells into the urethra, where it mixes with sperm and other fluids to make semen.
Glandular cells, which produce a milky fluid that liquefies semen.
Stromal cells (which form the structure of the prostate).

The central area of the prostate that wraps around the urethra is called the transition zone. The entire prostate gland is surrounded by a dense, fibrous capsule.

Functions of the Prostate Gland

The prostate gland provides the following functions:

The glandular cells produce a milky fluid, and during sex the smooth muscles contract and squeeze this fluid into the urethra. Here, it mixes with sperm and other fluids to make semen.
The prostate gland also contains an enzyme called 5 alpha-reductase that converts testosterone to dihydrotestosterone, another male hormone that has a major impact on the prostate.

Changes During the Lifespan

The prostate gland undergoes many changes during the course of a man's life. At birth, the prostate is about the size of a pea. It grows only slightly until puberty, when it begins to enlarge rapidly, attaining normal adult size and shape, about that of a walnut, when a man reaches his early 20s. The gland generally remains stable until about the mid-forties, when, in most men, the prostate begins to enlarge again through a process of cell multiplication.

HOW SERIOUS IS PROSTATE CANCER?

Prostate cancer is the most common male cancer in the US. Only lung cancer causes more cancer deaths in American men. The lifetime probability of developing prostate cancer is 8%. Each year, approximately 180,000 men in the United States will be diagnosed with prostate cancer, and about 32,000 will die from the disease. It should be noted that because older men often die while suffering from both prostate cancer and other serious medical disorders, official records may attribute many deaths to prostate cancer that are actually due to other causes. Some researchers believe that deaths caused by prostate cancer are misreported (mostly overdiagnosed) by as much as 10% to 20%.

Prognosis After Early Detection

Because so many prostate tumors are low-grade and slow growing, survival rates are excellent when prostate cancer is detected in its early stages. Cure rates are as high 98%.

Prognosis After Late Detection

Locally Advanced. If the disease is at a stage known as locally advanced, in which it has spread beyond the prostate but only to nearby regions, it is more difficult to cure, but survival rates can be prolonged for years in many men. (When cancer has metastasized to the pelvic lymph nodes, the outlook is worse than if it spread to other areas.)

Metastasized Cancer. If prostate cancer has spread to distant organs (metastasized), average survival time is one to three years, but some of these patients may live longer or die of other causes.

Prognosis After Recurrence

If cancer recurs after initial treatment for early-stage tumors, it is still potentially curable if it is contained within the prostate, although in most cases the cancer has spread. Hormone treatments for such recurring cancers can often prolong survival for years, although the cancer almost always returns again.

WHAT ARE THE RISK FACTORS FOR PROSTATE CANCER?

The incidence of prostate cancer rose dramatically between 1976 and 1994, particularly in younger men, in large part because of early detection with the use of more accurate screening tests. In determining risk factors for prostate cancer, a recent analysis of major cancers suggested that heredity might play a critical role in many prostate cancer cases. There has been somewhat less evidence for a major role from lifestyle or other environmental factors in prostate cancer than in some other major cancers (breast, lung, and stomach).

Hormones and Prostate Cancer

It is clear that hormones play a critical role in prostate cancer, but researchers have not yet fully clarified the specific hormones that may contribute to the disease. Some hormones under investigation include the following:

In a 2001 study of 17 hormones, none were associated with prostate cancer risk except one called androstanediol glucuronide, which at certain levels suggested a lower risk.

One study found a higher risk with increasing testosterone and a lower risk with increasing estrogen levels.

Dihydrotestosterone (DHT) is the principal male hormone in the prostate gland. It affects the size of the prostate gland itself and may play a role in prostate cancer.

Sex hormone-binding globulin (SHBG) binds to male hormones and leaves less available to stimulate prostate cell growth. High levels, then, are associated with protection against prostate cancer.

Insulin-like growth factor-I is a hormone that may increase the risk for prostate cancer.

Age

Prostate cancer occurs almost exclusively in men over the age of 40 and is still rare until age 50. Almost half of all men under 70 have at least microscopic prostate tumors. By age 80 to 90, 70% to 90% of men have evidence of microscopic disease.

Ethnicity and Being African American

African American men have the world's highest risk for prostate cancer, more than 50% higher than the risk for Caucasian American males. The disease is also far more lethal among African Americans. A number of factors may explain these differences.

Socioeconomic Issues. Socioeconomic factors may contribute to higher mortality rates in African Americans. For example, a 2000 study at a Veterans hospital where all the men had equal care reported no differences in tumor properties between African American and Caucasian men. The study suggests that African Americans have no higher risk for aggressive tumors, and their higher mortality rates are likely to be due to socioeconomic factors, such as lack of insurance, irregular screening and a late diagnosis, and unequal access to health care. Still, biologic factors still appear to play a role in the ethnic differences for the risk for prostate cancer itself and possibly in the severity of the cancer. For example, prostate cancer rates among Native Americans and Hispanic Americans are lower than those for Caucasians, despite their social and economic disadvantages.

Dietary Factors. Dietary or other environmental factors may play some small role in ethnic differences. This is suggested by the fact that, in spite of the high incidence in African American men, prostate cancer is rare in many parts of Africa. As another example, when Japanese men move to the US and adopt Western dietary habits, their risk for prostate cancer increases.

Differences in PSA Results. Research has suggested that African men may have higher prostate-specific antigen (PSA) levels than Caucasian men in their own age groups. This suggests that the current screening standards for PSA levels are less accurate for African Americans, although a 2001 study suggested that the known differences are minor and do not yet justify race-specific testing standards.

Insulin-Like Growth Factor Binding Protein (IGFBP3). A study reported that African American men have lower levels than Caucasian men of a protein called insulin-like growth factor binding protein 3 (IGFBP3), which may protect against cancer. (Insulin-like growth factor-I is a hormone that may increase the risk for prostate cancer in any man.)

Family History and Genetics

Men with a family history of the disease have a significantly higher risk of developing prostate cancer. For a man whose father had prostate cancer, the risk is about two and one-third times normal. The brother of a prostate cancer patient may face four and a half times the normal risk of developing prostate cancer. A number of genes are under investigation. Some genetic defects are inherited, but other mutations may be acquired after environmental or biologic assaults over a man's lifetime.

ELAC2. Researchers have identified a gene, called ELAC2, that may play a role in 2% to 5% prostate cancers. One variation puts men at moderate risk for prostate cancer and the other at significant risk (5 to 10 times). .

BRCA2. There is some evidence that mutation of the BRCA2 gene may carry a risk for prostate cancer in men, although in a very small fraction of patients. (This gene is associated with breast and ovarian cancers in women.) Previous research has found a higher risk of prostate cancer among men with a family history of breast or ovarian cancer, although a 2000 study did not find such a link, at least with breast cancer.

HPC1. Researchers have identified a gene called HPC1, which has been associated with 30% of inherited cases. A genetic abnormality that causes overproduction of a protein called Ret may prove to be implicated in some prostate cancers.

Androgen Receptor Gene. Variations in the gene that regulates the receptor for androgen are associated with prostate cancer and also with changes in PSA levels. They also may help explain some of the differences in risk between African Americans and other ethnic groups.

Mutations in Tumor Suppressing Genes. Mutations in genes that ordinarily suppress tumors, such as PTEN and p27, may play a role in some non-inherited cases.

Vasectomy

Studies investigating the relationship between vasectomy and prostate cancer have been conflicting:

A number of studies have reported some association between vasectomy and a higher incidence of prostate cancer. Two of the most recent ones were Canadian studies in 2000 and 2001. The 2001 study reported a higher risk beginning 10 years following the procedure.
A 1999 study that specifically investigated a possible association between vasectomy and prostate cancer found no link. In fact, men with vasectomy who did have prostate cancer were more likely to be diagnosed at an earlier stage and with a less aggressive prostate tumor.

None of the studies reporting higher rates of prostate cancer in men with vasectomies can exclude the possibility that they may simply be due to earlier prostate screening in men who have had vasectomies. Research on the relationship with prostate cancer is continuing, although if any link is found, it is likely to be very weak.

Chemical Exposure

Men whose work involves heavy labor and those exposed to certain metals and chemicals, including cadmium, dimethylformamide, and acrylonitrile, may be at higher risk for prostate cancer. Some studies have indicated that farmers might be at higher risk.

A 2001 study of data collected between 1979 and 1985 concluded that certain leisure activities may expose men to the same chemicals as those that pose a possible danger in the industrial setting. They included the following:

Home or furniture maintenance
Painting, stripping, or varnishing furniture
Activities that involve exposure to lubricating oils or greases, metal dust, or pesticides or garden sprays

Obesity

Although a Western lifestyle is associated with prostate cancer, a direct causal role for either obesity or dietary fats has not been established. [See What Dietary Factors Are Associated with Prostate Cancer Risk and Protection?] A 2001 study did find obesity to be associated with a modest increase in prostate cancer mortality, although not with the risk for prostate cancer itself. In a previous study of Chinese men, however, it was not obesity itself but an unhealthy fat distribution that was associated with a higher risk. High-risk individuals in the study were those whose fat was more centered in the abdomen, the so-called apple-shape. This higher waist-to-hip ratio is also a risk factor for diabetes. Such findings have led experts to investigate two hormones, leptin and insulin-that are associated with both obesity and diabetes. Either of these hormones could theoretically stimulate prostate cancer growth. In another 2001 study, moderate (not high levels) of the hormone leptin was linked to prostate cancer, suggesting that there may be a critical fat mass that is predisposed to the disease. [ See also Diet under How Can Prostate Cancer be Prevented, below.]

Other Factors Associated with Prostate Cancer

Active Sexual Life. A lthough some studies have suggested that an active sexual life may increase the risk for prostate cancer, most studies refute this possibility. One study found that the risk for Catholic priests was no lower than in sexually active men.

Nonmelanoma Skin Cancers and Sunlight. One study reported that patients with prostate cancer and a history of nonmelanoma skin have a higher risk for a poorer outlook. Such skin cancers are highly associated with exposure to sunlight. It should be noted, however, sunlight triggers production of vitamin D in the body, which may help protect against prostate cancer. Prostate cancer rates are, in fact, lower in southern, sunny regions.

Infection. Some association has been seen between prostate cancer and infections, such as bacterial prostatitis, and some viral infections, including those caused by herpesvirus, human papillomavirus, and cytomegalovirus. No link has been proven and a study found no relationship with papillomavirus. Although some of these agents are sexually transmitted, the association with sexual activity is still unclear; one study even found a lower rate of prostate cancer in men with a history of sexually transmitted diseases.

WHAT DIETARY FACTORS ARE ASSOCIATED WITH PROSTATE CANCER RISK AND PROTECTION?

Although microscopic evidence of prostate cancer appears to be similar in men around the world, its progression differs with location. For example, men who live in Asia have a lower incidence of clinically apparent prostate cancer than Asians who move to America. Diet may play some role, although it is not yet clear if there is any protective diet. It is important to note that the effects of the foods and food substances discussed below on prostate cancer risk require further investigation, and any evidence on their effects is very weak. A major study is underway to determine the cancer-protective effects of selenium, vitamin E, and low fat diets.

Fats

Some studies have found some association between high fat-intake and prostate cancer. A 1999 study found no association between intake of any major fats, including saturated (animal fats) and unsaturated fats (vegetable oils). More intensive research however is investigating specific fatty acids, compounds that make up fats, which may clarify the role of fats.

Oily Fish and Omega-3 Fatty Acids. Some research has suggested that omega-3 fatty acids, which are plentiful in dark, oily fish, may be protective. A study in Sweden found that men who ate little or none of such fish (e.g. salmon, sardines, halibut, swordfish, and tuna) were twice as likely to develop prostate cancer as those who ate two or more servings a week. Omega-3 fatty acids also may combat heart disease, and have shown promise against cancers of the colon, rectum and ovary.
Alpha-Linolenic and Omega-6 Fatty Acids. On the other hand, some research has indicated that alpha-linolenic acid and total omega-6 fatty acids may increase the risk of prostate cancer. Sources of these fatty acids are the polyunsaturated vegetable oils (e.g., corn, safflower, soybean, canola, and sunflower oil), which constitute most of the oils consumed in the US.

It should be noted that some dietary intake of all of these fatty acids is important for health. Research suggests, however, that our current Western diet contains an unhealthy high ratio (10 to 1) of omega-6 to omega-3 fatty acid, and that a better balance may be beneficial.

Soy

A number of studies have suggested that soy may be protective, which may partially explain the low rate of prostate cancer observed in Japanese men. Soy is a rich source of an estrogen-like plant compound that has been shown in laboratory studies to inhibit hormones that promote prostate cancer.

Fruits and Vegetables

Diets high in fresh fruits and dark-colored vegetables are known cancer fighters. Specific vegetables that may be particularly important for preventing prostate cancer include cooked tomatoes, which are high in a beneficial plant chemical called lycopene, and cruciferous vegetables such as cauliflower and broccoli. Boron-rich fruits may also be protective. They include red grapes, avocados, and dried fruits.

Whole Grains and Nuts

Whole grain cereals, seeds, and nuts appear to be protective. Part of this protection may be due to their high fiber content. Fiber binds to sex steroids and is excreted, carrying the hormones with it. Whole grains contain selenium [ see below ], a rare element that may have some protective properties. And nuts contain boron, which may also protect against prostate cancer.

Vitamins and Minerals

Calcium and Vitamin D. One 2000 study reported an association between consuming large amounts of dairy products and a modestly increased risk for prostate cancer. One possible basis for this finding is some evidence that calcium (contained in dairy products) can lower levels of the most active form of vitamin D (1,25 dihydroxyvitamin D), which may help protect against prostate cancer. In fact, some research is focusing on prostate treatments using vitamin D analogs. There is still no clear proof, however, that high calcium and low vitamin D levels pose a significant risk for prostate cancer.

Vitamin E. A large 1998 trial of male smokers found that long-term daily use of 50 mg of vitamin E markedly decreased the incidence and mortality of prostate cancer. It had no protective effect for men who already had prostate cancer. One major study suggests the possible benefit of vitamin E is confined strictly to smokers or recent quitters. Other, more recent studies suggest that specific natural forms of vitamin E, such as gamma tocopherol or vitamin E succinate, might have anti-cancer benefits and warrant more study. (The form of vitamin E in most supplements is dl alpha tocopherol, a synthetic form.)

Selenium. In laboratory studies, selenium has acted directly on prostate cancer cells, stimulating cell death and inhibiting growth. Studies on actual significant protection from selenium supplements against prostate cancer, however, have been weak. In one study, men who took a 200 mcg daily supplement had a lower incidence of prostate cancer. It should be noted that high amounts of selenium can be toxic, and can cause hair and nail loss.

Zinc. Zinc is of interest because it accumulates to the highest levels in a man's body in either a normal prostate or one enlarged from benign prostate hyperplasia. It may be important for prostate health, although its effects are still not clear.

Curcumin (Turmeric)

Curcumin, also known as turmeric, is a common yellow seasoning in Indian and other Southeast Asian countries. Interesting laboratory studies have suggested that it significantly inhibits the growth of prostate cancer. To date, however, animal studies have not reported any protection.

Alcohol

Moderate to heavy alcohol intake (22 to 56 drinks a week) has been associated with increased risk.

WHAT NONDIETARY MEASURES CAN HELP PREVENT PROSTATE CANCER?

Exercise

Exercise is beneficial for general health and it temporarily lowers testosterone levels. Studies on its effects on prostate cancer are mixed. It may not have much effect on men who are at low risk to begin with. A 1998 study suggested that although exercise had no protective effect overall on prostate cancer, vigorous exercise was associated with a lower risk for metastatic prostate cancer. Exercise in any case is an important component in any health-protective program.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

There is some evidence from animal studies that nonsteroidal anti-inflammatory drugs (NSAIDs) have properties that offer some protection against prostate cancer. NSAIDs suppress chemical in the body called COX-2, a protein that may cause prostate cancer cells to spread. Standard NSAIDs include aspirin, ibuprofen (Advil), and naproxen (Aleve, Naprosyn, Naprelan, Anaprox). More powerful NSAIDs, such as sulindac (Clinoril) are available by prescription and are being studied for protection. Newer agents, such as celecoxib (Celebrex), rofecoxib (Vioxx), and meloxicam (Mobic) only suppress COX-2 and may warrant specific investigation. Human studies on the protective value of NSAIDs are weak to date, and they may be helpful only in specific individuals.

WHAT ARE THE SYMPTOMS OF PROSTATE CANCER?

Prostate cancer usually causes no symptoms in the early stages. As the malignancy spreads, it may constrict the urethra and cause urinary problems. Later-stage symptoms typically include:

Weak urinary stream.
Inability to urinate.
Blood in the urine.
Interruption of urinary stream (stopping and starting).
Frequent urination (especially at night).
Pain or burning during urination.

Bone Pain

The development of significant pain in one or more bones may herald the occurrence of bony metastases. This chronic pain occurs most often in the spine and sometimes flares in the pelvis, the lower back, the hips, or the bones of the upper legs. It may be accompanied by significant weight loss.

WHAT OTHER CONDITIONS HAVE SYMPTOMS SIMILAR TO PROSTATE CANCER?

Benign Prostatic Hyperplasia (BPH)

In up to half of men in their fourth decade, the prostate begins to enlarge through a process of cell multiplication called benign prostatic hyperplasia (BPH). The symptoms of BPH can mirror late-stage prostate cancer because the enlarging inner portion of the prostate puts pressure on the urethra, which can potentially cause urinary problems. About 80% of men eventually develop enlarged prostates, but only some experience significant symptoms. BPH is a normal condition and is not life-threatening. [ For more information, 71, Benign Prostatic Hyperplasia .]

Relationship to Prostate Cancer. Because the prostate enlargement in BPH is affected by testosterone, many men are concerned that it may be related to prostate cancer. Fortunately, current evidence indicates that it has no effect one way or the other. The two conditions develop in different parts of the prostate. BPH occurs in the inner zone of the prostate, while cancer tends to develop in the outer area. A ten-year study found no higher risk for prostate cancer in men with BPH.

Prostatitis

Prostatitis is an inflammation of the prostate, often caused by bacterial infections. Symptoms include urgency, frequency, and pain in urination, sometimes accompanied by blood in the urine or fever.

WHAT TESTS ARE USED TO SCREEN AND DIAGNOSE PROSTATE CANCER?

Indications for Annual Screening

The American Cancer Society and the American Urological Association (AUA) recommends annual screening in the following:

Annual screening should start in most men aged 50 to 70. (Based on a computer model, however, some experts recommend testing all men at ages 40 and 45 then every two years from age 50 on. Such a protocol, the model suggests, would be more cost effective and prevent more deaths than the current screening schedule.)
Most experts agree that men with a family history of prostate cancer and all African-American men should start screening at about age 40.

Standard Screening Tests for Early Detection

Currently, two standard tests are used for early detection of prostate cancer:

A digital rectal exam (DRE), in which a physician palpates the prostate in order to feel lumps or masses.
A blood test that measures the level of a protein produced in the prostate known as prostate-specific antigen (PSA).

PSA is currently considered the best single test for early prostate cancer detection, although the DRE will sometimes detect tumors in patients who have normal PSA levels. There is considerable controversy, however, surrounding the value and accuracy of these tests for early detection of prostate cancer. [ See Box Accuracy of Screening Tests.]

If the digital rectal examination indicates the presence of cancer, regardless of the PSA results, a physician may also obtain a visual image of the prostate through an ultrasound procedure called transrectal ultrasonography (TRUS).

Only a biopsy, however, in which a tiny sample of prostate tissue is surgically removed, can actually confirm a diagnosis of prostate cancer. Other tests are being developed, such as the so-called free PSA test, that may improve accuracy.

Digital Rectal Exam (DRE)

About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities. The exam is quick and painless but some men find it embarrassing. It is not very accurate in detecting early cancers but studies indicate that regular DREs still save lives. [ See Box Accuracy of Screening Tests.]

PSA Test

PSA is a protein produced in the prostate gland that keeps semen in liquid form. Prostate cancer cells appear to produce the protein in elevated quantities. Measuring PSA levels, then, increases the chance for detecting the presence of cancer when it is microscopic. Elevated or reduced levels of PSA can be used for guidelines only, however. The test is not accurate enough to either completely rule out or confirm the presence of cancer. [ See Box Accuracy of Screening Tests.]

Factors Affecting Accuracy. A number of factors and noncancerous conditions can influence PSA levels:

Ethnicity. Normal levels in Caucasian males may be different from those for African-American or Asian men. Some experts believe that there should be different scales for determining risk among these groups, but there is still not enough information to support a specific range for various ethnic groups.
Age. PSA levels tend to rise naturally with age, so an elevated level in a man who is 70 may be less serious than the same level in a younger man. Some experts believe that men over 65 years old who have low PSA levels are at such low risk for prostate cancer that they may be able to forego further testing.
Benign Prostatic Hyperplasia (BPH) and Its Treatments. Between 25% to 56% of patients with BPH have elevated levels. Certain surgical treatments for this condition can also elevate PSA. On the other hand, the drug finasteride (Proscar) may reduce PSA levels, so that cancer might be missed.
Prostatitis. About half of men with elevated PSA levels but no signs of cancer on biopsy have signs of prostatitis as indicated by urine and prostate secretion tests. (Prostatitis simply means inflammation in the prostate. Inflammation is usually due to bacterial infection but it can also be caused by nonbacterial factors.) In one study, screening for prostatitis increased the accuracy of the PSA test significantly and reduced the number of unnecessary biopsies.
Other Noncancerous Conditions. Other noncancerous conditions that can increase PSA levels include surgical procedures for BPH, acute urinary retention, digital rectal examinations (DREs), and prostate biopsies themselves.
Ejaculation. Ejaculation within 48 hours can raise PSA levels, although one study suggested that this occurs only when PSA levels were already elevated.

Even with its limitation, the PSA test has increased the number of detectable early-stage and therefore treatable cancers. In one study, centers reported that between 1987 to 1995 cancers detected in very early stages increased from 2.1% to 36.4%, while advanced cancer rates declined from over 25% to under 6%. Because of the slow-growing nature of prostate cancer, however, it is not known whether all of these very early cancers will result in significant or life-threatening disease.

PSA Tests and Effects on Mortality Rates. It is not yet confirmed that PSA tests actually save lives, although studies are promising. Deaths from prostate cancer, for instance, have declined in the US and European countries where screening is common, which might be due to earlier diagnoses and treatment at localized stages. Such studies, however, lack confirming evidence that these reductions in mortality rates are directly due to early screening or to other factors, such as improvements in risk factors. Moreover, prostate cancer death rates have also declined in England and Wales, where PSA screening is not widely practiced. In addition, while early detection has increased cancer diagnosis by about 80 per 100,000 men in the US, the death rate has declined by only 4 per 100,000 and is still greater than in the 1970s and 1980s.

PSA Test Variations

To improve the accuracy of the PSA tests, particularly when PSA levels fall between 4 and 10 ng/mL, researchers are developing methods for measuring other factors. To date, no test has emerged as clearly superior to the PSA test.

Free PSA Test. A small amount of prostate specific antigen leaks out of the prostate into the bloodstream. There, PSA can circulate without bonding and is referred to as free PSA. It can also form chemical combinations with other proteins. If cancer is present, PSA is more likely to be bound, and so there is less free PSA in circulation. The free PSA blood test, then, is a ratio of free PSA to the total PSA (free PSA plus chemically bound PSA).

The following results are used to determine the presence or absence of cancer:

A free-to-total PSA ratio of 20% or lower plus total PSA levels of 4 to 10 ng/mL are strongly suggestive of prostate cancer. (Some experts use 25% as a cut-off, but studies suggest that using this cut-off would miss cancers in many African American and older men.)
A free-to-total PSA level of over 20% plus normal or even moderately elevated total PSA are more likely to indicate the presence of other, benign conditions, such as benign prostatic hyperplasia.

A 2000 report suggested that testing free PSA may improve prostate cancer detection by roughly 40%. In addition, any cancers that the test missed would not develop into significant disease for at least nine years, providing ample opportunity to identify them before they became serious. Not all studies support its advantages over total PSA, however. For instance, a 2001 study compared repeated screening tests using total, free, and complexed PSA [ see below ]. Its results suggested that total PSA was more accurate in predicting prostate cancers than the other two.

Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating PSA that is bound to a molecule termed alpha1-antichymotrypsin. It represents about 90% of the total PSA in men and is significantly higher in men with prostate cancer than in those with BPH. To date, studies have reported conflicting results on its benefits for diagnosing prostate cancer.

Ultrasound (Transrectal Ultrasonography)

An ultrasound procedure called transrectal ultrasonography (TRUS) provides a visual image of the prostate and is used if the DRE indicates the presence of cancer. Ultrasound is not effective as a diagnostic tool by itself because it cannot differentiate very well between benign inflammations and cancer, but the procedure may help to confirm an uncertain preliminary diagnosis and is useful as a guide for needle biopsies. Ultrasound enhancements, such as Doppler imaging or computer modeling techniques called artificial neural networks (ANN), may increase the accuracy of TRUS.

Indications for Biopsy and Follow-Up

Some physicians would consider performing a biopsy to confirm a diagnosis of prostate cancer after screening tests report the following results:

PSA level of 4.0 ng/mL or higher.
PSA level that has increased significantly from one test to the next.
Abnormal digital rectal examination (DRE).

These guidelines, however, are not cut in stone. In most cases, abnormal levels do not mean that a man has cancer and normal levels do not always mean a man is cancer-free. For example, biopsies in the majority of men with elevated PSA levels show no cancer after biopsy. (This does not necessarily mean these men are cancer-free. Biopsies, too, can miss cancers, particularly when tumors are very small.) A 2000 study concluded that the best indicator for a biopsy was a combination of a positive PSA and DRE result in an older man, rather than any one test taken alone. And, there is some evidence that each test may detect cancers that the other doesn't. Researchers in a major European study, however, are recommending biopsies without a DRE for PSA readings of 3 ng/ml and above. [ See Box Accuracy of Screening Tests.]

Between 85% and 92% of men have PSA levels below 4.0. In such cases, some experts recommend follow-up in these cases:

DRE and PSA screening every three years for PSA levels lower than 1.0 ng/ml. (DRE at these levels are more useful than PSA in detecting cancer.
Annual PSA screening for levels 1.0 to 3.0 ng/ml.

Accuracy of Screening Tests
	PSA alone	DRE alone	Combination
Risk of Cancer with Abnormal Results	About 2% or less chance of cancer for readings below 3 ng/ml. Between 17% and 50% chance of cancer for readings 3 to 10 ng/ml. Very strong chance above 10 ng/ml.	Less than 20% chance for cancer with abnormal results. Unfortunately, up to 70% of cancer detected with DRE alone have already spread beyond the prostate gland.	Over 60% chance for cancer with abnormal results.
Risk of Missed Cancers with Normal Results	Between 9% and 37% of prostate cancers are present in men with PSA levels below 4 ng/ml and no indications from a DRE.	About 60% of cancers are missed.	NA

Biopsy

Initial Biopsies. If preliminary tests raise the suspicion of cancer, physicians will perform a biopsy. Biopsy is used to diagnose prostate cancer, and is a very accurate method for predicting the severity of an existing cancer.

Core Biopsy. The standard method is called a core biopsy, which uses a spring-loaded biopsy device inserted into the rectum. The device propels a needle into the prostate, obtaining a core of tissue, which is examined by pathologists.
Fine Needle Aspiration. A more recent procedure called fine needle aspiration is less painful and may be as accurate as a core biopsy if the sample obtained is sufficient for analysis and if it is analyzed by a skilled pathologist.

More than half of the men who have a biopsy experience discomfort and anxiety, with men under 60 reporting higher levels of discomfort than older men. Taking a sedative an hour or two before the procedure can help reduce distress. Complications of biopsy are low, but urinary tract infection, fever, or bleeding occurs in 0.1 to 4%.

Repeat Biopsies. Because a biopsy can miss very small cancer cells, sometimes three or even more biopsies are recommended if PSA levels are very high. Repeat biopsies are indicated if initial results do not detect any cancer but any of the following are true:

PSA levels are abnormally high. One study suggested that patients with free PSA less than 30% or transition zone PSA density of 26% or greater should have repeat biopsies. (Free PSA was the most accurate predictor of prostate cancer for repeat biopsy patients.)
DRE results are abnormal [ see above ].
Ultrasound results are abnormal [ see above ].
The initial biopsy yields microscopic findings that are suspicious.
The initial biopsy detects precancerous cells known as high-grade prostatic intraepithelial neoplasia (PIN). No treatment is necessary with this finding, but these patients should be rechecked every three to six months for the next two years, and then annually.

In a 2001 study, in men with PSA levels of 4 to 10 ng/mL who did not show signs of cancer on the first biopsy, the following cancer rates were reported on subsequent biopsies:

Second biopsy: 10% cancer rates.
Third biopsy: 5%
Fourth biopsy: 4%.

The cancers found in biopsies 3 and 4 tended to be nonaggressive with favorable outlooks.

Investigative Screening Tests

Transition Zone PSA Test. Some tests have been developed to measure the density of the PSA in the transition zone of the prostate gland. (The transition zone is the central area of the prostate that wraps around the urethra, the tube that carries urine down through the penis.) One study reported that a PSA density of 35% predicted prostate cancer in 90% of cases. A combination of free PSA and transition zone PSA may be particularly useful.

Human Glandular Kallikrein 2 (hK2), Human glandular kallikrein 2 (hK2) is a chemical cousin of PSA. HK2 testing seems to do a better job than testing for total and free PSA for discriminating between cancers that are confined to the prostate and those that have spread to other locations.

Urine Test for Hypermethylation. A condition known as hypermethylation is an early genetic change that occurs in 90% of prostate cancers. Hypermethylation is caused by the glutathione-S-transferase (GSTP1) gene and it is not found in normal cells or in men with benign prostatic hypertrophy (BPH). Tests to detect this condition are in development.

Tests for Insulin-like-Growth Factor. Insulin-like growth factors have been implicated as possible triggers of cancer cell growth. Levels of these growth factors may provide information on future cancer risks, particularly in African American men. More research is needed in this area, however.

WHAT TESTS INDICATE THE EXTENT OF EXISTING PROSTATE CANCER?

PSA Levels

Once cancer is diagnosed, PSA levels may help to determine its extent. If PSA levels are less than 20 ng/ml, then it is possible that the cancer has not spread to distant sites. PSA levels over 40 ng/ml is a strong indicator that cancer has metastasized (has spread to sites that are distant from the origin, in this case the prostate gland). PSA levels are also monitored after initial treatments for prostate cancer. Rising levels indicate recurrence, although the cancer may not recur for a long time, and the location of the new cancer cannot be determined using PSA testing. Measuring the free PSA percentage before surgery may prove useful for determining outcome. One study indicated that the higher the percentage, the less aggressive the disease. [ For more details, see What Tests Are Used to Diagnose Prostate Cancer? , above .]

Biological Markers

A number of biological factors are being used or investigated as markers for cancer or its severity.

Chromosomal Sets. The number of chromosomal sets in the nucleus of the tumor's DNA, known as its ploidy, is an important marker for patients in late stages of prostate cancer. Tumors with the normal two sets of chromosomes, called diploid tumors, usually have a more favorable outcome than tumors that have four sets of chromosomes (tetraploid tumors) or have an abnormal number of individual chromosomes (aneuploid tumors).

Blood Vessel Density. The density of blood vessels in the tumor is an important indicator of outcome. The greater the density, the more likely the tumor is to be aggressive.

Testosterone Levels. Higher total testosterone levels may increase the risk for metastasis. A 2000 study found an association with low free testosterone and more extensive prostate cancer, suggesting it could be a marker for aggressive disease. (Free testosterone, as with free PSA, is not chemically bound.)

Other Markers, Other markers being investigated for predicting cancer progression include prostate-specific membrane antigen, prostatic acid phosphatase, growth factors, and genes that regulate tumor growth (eg, p53, p27, bcl-2).

Nuclear Imaging Tests

The ProstaScint is a scanning technique that uses tiny amounts of radioactive material with a monoclonal antibody that can attach specifically to prostate cancer cells. A special camera then can detect tumor cells that cannot be detected with other diagnostic tools. It may be effective in helping physicians make better treatment decisions. In a 2000 study, 90% of patients who underwent ProstaScint scanning had a successful treatment outcome (determined by normal or below normal PSA levels) compared to 60% of patients who did not undergo scanning. The role of this test in the routine management of prostate cancer is still being defined.

Tests for Metastasis

If the biopsy indicates cancer, the physician will order other tests to determine whether or how far the cancer has spread.

Bone Scans and X-Rays. Bone scans and x-rays may reveal whether the cancer has invaded the bones. To perform a bone scan, physicians inject low doses of a radioactive substance into the patient's vein, which accumulates in bones that have been damaged by cancer. A scanner then reveals how much of the radioactive material has accumulated. Arthritis and infections may also produce positive scans. Patients with PSA levels below 20 ng/mL are unlikely to have scans that show cancer in the bone.

Computed Tomography and Magnetic Resonance Imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) scans can further pinpoint the location of cancer that has spread beyond the prostate.

Bone Metastasis Markers. Researchers are investigating chemical markers, such as a amino-terminal propeptide of type I procollagen (PINP), as early indicators of bone metastasis.

HOW ARE PROSTATE CANCER TUMORS STAGED AND GRADED?

Researchers are continually searching for methods to determine how aggressive individual prostate cancers are so they can choose the best treatments. As an aid, experts have devised different classification systems that help assess the properties of the cancer. These systems include staging and grading the tumors and measuring PSA levels. In general, the higher the stage, grade, and PSA numbers, the more severe the condition and the more aggressive the treatment. Current classifications systems have significant limitations in guiding treatment choices. Newer tests, markers, and imaging techniques may eventually improve the accuracy of staging categories.

Staging Systems

A tumor's stage is an indication of how far it has spread from its original site. Cancers are staged according to whether they are still localized (remain surrounded by healthy cells) or have spread beyond the original site. Two prostate cancer staging systems are commonly used: the TNM system and the Jewett system. To avoid confusion, this report only uses the TNM system. The TNM system is explained in detail, and the Jewett system is explained in reference to the TNM system.

TNM Staging System

The TNM system refers to clinical tumor stages as:

_ T for tumor.
_ N for regional lymph nodes.
_ M for metastasis (tumors developing outside the prostate).

T Stages

T followed by numbers 0 through 4 refers to the size and extent of the tumor itself.

Stage	Description
T1	The tumor cannot be felt or seen using imaging techniques.
T1a	Cancer cells are incidentally found in 5% or less of tissue samples from prostate surgery unrelated to cancer.
T1b	Cancer cells found in more than 5% of samples.
T1c	Cancer cells identified by needle biopsy, which is performed because of high PSA levels.
T2	The cancer is confined to the prostate but can be felt as a small well-defined nodule.
T2a	Tumors are in half a prostate lobe.
T2b	Tumors are in more than half a lobe.
T2c	Tumors in both lobes.
T3	The tumor extends through the prostate capsule.
T4	The tumor is fixed to or invades adjacent structures.

N Stages

N followed by 0 to 3 refers to whether the cancer has reached the regional lymph nodes, which are located next to the prostate in the pelvic region.

Stage	Description
N0	Regional lymph nodes are still cancer-free.
N1	A small tumor is in a single pelvic node.
N2	A medium-size tumor is in one node or small tumors are in several nodes.
N3	A large tumor is in one or more nodes.

M Stages

M stages refer to metastasis (tumors developing outside the prostate).

Stage	Description
M0	Metastasis has not occurred (cancer has not spread beyond the regional lymph nodes).
M1a	Cancer has spread to lymph nodes beyond the regional lymph nodes.
M1b	Cancer has invaded the bones.
M1c	Cancer has spread to other sites.

Jewett Staging System

The stages in the Jewett system are roughly equivalent to the stages in the TNM system as follows:

Jewett Stage	TNM Stages
A	T1
B	T2
C	T3, T4
D	N1, N2, N3, M1

The Gleason Grading System

Tumors are graded according to a scale known as the Gleason system, which measure how well or poorly organized they are under the microscope. Two-thirds of prostate cancers have a mix of tumor grades. The cancer is then scored by adding the totals of the primary tumor grades.

Grade 1: Single, well-packed tumors.
Grade 2: Single, more loosely arranged and less uniform tumors.
Grade 3: Single tumors of different sizes and patterns, with cellular breakdown becoming increasingly worse.
Grade 4: Irregular tumor masses, fused together. May show clear cells.
Grade 5: the tumors have broken down and cellular structure has markedly deteriorated.

To determine a prognosis, the tumor grades are then added together for a final score. For example, a tumor with primarily 3 and 4 grade tumors is given a score of 7. The following scores are often used to suggest how well or poorly the tumor is differentiated. The higher the score, the more severe the break-down of their cellular structure and the more likely they are to spread aggressively:

Score 2-4: Well-differentiated. Indicates about a 95% chance for surviving 15 years without aggressive treatment.
Score 5-6: Moderately well differentiated. Slightly lower chance of survival that decreases with time.
Score 7-10: Moderately poorly to poorly differentiated. 15-year survival rates of 15% to 40%.

WHAT ARE THE TREATMENT OPTIONS FOR PROSTATE CANCER BY GRADING AND STAGING CATEGORIES?

Experts have devised treatments based on classification systems, including staging and tumor grade.

Stage I

Tumors: T1, N0, M0, G1, Stage A. Treatment Options. Watchful waiting, with hormone treatment if symptoms develop. Surgery (radical prostatectomy or cryosurgery). Radiation treatment (either external-beam irradiation or interstitial implantation in selected patients). For reducing mortality rates, no strong evidence supports one treatment choice over another; survival rates appear to be equivalent and close to normal. Treatment may be considered in men under 60, particularly those with tumors classified as T1b, in which cancer cells are found in more biopsy samples than in T1a. Postoperative radiation treatment may be considered if surgery reveals high risk for recurrence. Radiation with hormone therapy is under investigation for intermediate and high-risk groups.

Stage II

Tumors: T1, N0, M0, G2, 3, or 4. Treatment Options. Watchful waiting in selected patients (such as those with low-grade tumors). Surgery (radical prostatectomy usually with pelvic lymphadenectomy) or radiation therapy (external-beam irradiation or interstitial implantation in selected patients). Radiation treatment after prostatectomy may be considered to reduce local recurrence.

Tumors: T2, N0, M0, Any G, Stage A2, B1 or B2. Treatment Options. Careful watchful waiting in selected patients (such as those with low-grade tumors) followed by hormone treatment when symptoms occur. Radical prostatectomy or radiation treatment (external-beam irradiation or interstitial implantation in selected patients). Treatments have similar results for up to 10 years. Possible use of hormone therapy with radiation treatment. Cryosurgery under investigation. Neoadjuvant hormonal therapy followed by radical prostatectomy under investigation.

Stage III

Tumors: T3, N0, M0, Any G (Stage C), Treatment Options. External-beam irradiation using a linear accelerator is a commonly used treatment for most of these patients. Hormonal treatment (orchiectomy or androgen-suppressing drugs) along with radiation may improve survival rates from prostate cancer. Hormonal treatments alone. Clinical trials using other therapies. Careful observation in selected patients. (One study reported that in selected patients with low-grade tumors who chose watchful waiting, survival rates were 88% at five years and 70% at nine years.) Radical prostatectomy usually with pelvic lymphadenectomy considered in highly selected patients but, in general, surgery has very inferior results compared to radiation.

Treatments for Urinary Tract Symptoms. External beam radiation therapy. Hormonal manipulation. Transurethral resection of the prostate (TURP). Investigative radiation therapy using protons or neutron radiation. Investigative cryosurgery.

Stage IV

Tumors: T4, N0, M0, Any G; or any T, N1 through 3, M0, Any G; (stage D1 or D2) Treatment Options. Hormonal therapy, which may be one of the following: orchiectomy alone or with an antiandrogen; LHRH agonists, such as leuprolide; leuprolide plus an antiandrogen; estrogens. External-beam radiation possibly used with on-going androgen suppression treatment for attempted cure in highly selected MO patients. Radical prostatectomy with immediate orchiectomy under investigation. Systemic chemotherapy under investigation. Clinical trials using other therapies. Cure is rare in these patients but striking subjective or objective responses to treatment occur in many patients.

Treatments for Urinary Tract Symptoms. External beam radiation therapy. Hormonal manipulation. Transurethral resection of the prostate (TURP). Investigative radiation therapy using protons or neutron radiation. Investigative cryosurgery.
Pain Relief. Low dose prednisone (a corticosteroid) alone or with mitoxantrone (a chemotherapy agent) reduces inflammation and may help relieve pain.

Tumors: any T, any N, M1, Any G (stage D2). Treatment Options. Hormonal therapy, which may be one of the following: orchiectomy alone or with an antiandrogen; LHRH agonists, such as leuprolide; leuprolide plus an antiandrogen; estrogens. Cure is rare in these patients but striking subjective or objective responses to treatment occur in most patients.

Treatments for Urinary Tract Symptoms. External beam radiation therapy. Hormonal manipulation. Transurethral resection of the prostate (TURP).
Treatments for Symptoms of Bone Metastasis. R adiation therapy (external beam radiation or strontium-89 radioisotopes) or hormonal manipulation (orchiectomy or LHRH agonist drugs or both).
Pain Relief. Low dose prednisone (a corticosteroid) alone or with mitoxantrone reduces inflammation and may help relieve pain.

Recurrent Prostate Cancer

Treatment Options. Dependent on various factors: prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations.

Patients whose cancer recurs locally after prostatectomy: radiation therapy, hormonal therapy.
Patients whose cancer recurs locally after radiation therapy: hormonal therapy, prostatectomy (very select patients).
Patients whose recurrent cancer has spread see treatment options for Stage IV.

WHAT ARE THE GUIDELINES FOR TREATING LOCALIZED PROSTATE CANCER?

Guidelines for Choosing the Best Treatment for Localized Cancer

Choosing the best treatment for localized prostate cancer (T1 or T2) is generally based on the patient's age, the stage and grade of the cancer, and the patient's knowledge and acceptance of the risks and benefits of each therapy.

Patients have three main options:

Surgery (radical prostatectomy or cryosurgery) removes or destroys the prostate gland. The vessels that carry semen and surrounding tissue may also be removed. With cancer that has spread beyond the prostate, the pelvic lymph nodes are removed.
Radiation is used to destroy tumors.
Watchful waiting (for selected patients only) involves lifestyle change and careful monitoring to see if surgery or radiation becomes necessary.
even the medical community is divided over the best treatment for localized prostate cancer. No treatment appears to have a survival advantage. The choice is often not an easy one, even for experts, for many reasons.
of Data on Survival Rates. No studies to date have provided evidence strong enough so that patient and physicians can make confident choices between watch-and-wait and aggressive treatments. In general, no approach has emerged with a survival advantage. In the United Kingdom, radiation therapy is the most common treatment and mortality rates are similar to those in the US where surgery is the standard approach. In Sweden, watchful waiting is the most often chosen option and one study suggested that their mortality rates declined in parallel with a decline in aggressive treatments. However, experts argue that the biopsy techniques used in Sweden are more likely to result in false diagnoses of prostate cancer and the men in the study tended to be older than in other studies. A major well-designed study is underway to help resolve these questions.

Imperfection of Classification System, The classification systems are not perfect. For instance, even if tumors are rated in low stages and grades and are treated accordingly, undetected cancer cells may escape and spread beyond the prostate. [ See What are the Treatment Options for Prostate Cancer by Grading and Staging Categories?] Other factors, such as the man's age and medical condition, must be included in determining whether aggressive treatments or conservative measures are appropriate.

Specialty Bias. Patients should be aware that physicians may be biased to prefer a specific treatment depending on their specialty. For example, in one study the following treatments were favored for patients who were generally appropriate candidates for either surgery, radiation, or watchful waiting:

93% of urologists recommended radical prostatectomy.
72% of radiation oncologists recommended radiation. (And 82% thought that radical prostatectomy was overused.)

Virtually none of the physicians recommended watchful waiting. When in doubt, patients should always seek a second opinion to help them make this important choice.

Quality of Life. Surgery and radiation both have potentially distressing side effects, including the possibility of impotence, incontinence, or both. A man must then weigh his own emotional responses to the possibility of these side effects versus the possible stress of watchful waiting.

In general, differences in quality of life after surgery or radiation treatment have to do with the specific effects of each type of treatment. Studies report the following:

Radiotherapy generally causes more bowel problems than surgery does, 30% to 35% versus 6% to 7%, according to a 2001 study. In the same study, radiotherapy patients reported more physical and emotional limitations, although they tended to be older than the surgical patients. In another 2001 study, however, patients who underwent external radiation reported no significant decrease in quality of life throughout the study, which extended to a year after treatment. Those who underwent brachytherapy (radiation implants) reported a reduced quality of life during the first three months, but it returned to normal within a year.
Prostatectomy causes more urinary incontinence (39% to 49% versus 6% to 7% for radiotherapy patients) and more incidences of erectile dysfunction (80% to 91% versus 41% to 55%), according to a 2001 study. In another study in the same year, patients who underwent radical prostatectomy reported lower quality of life during the first month but it returned to normal by three months.
Watchful waiting imposes an emotional burden on any man who must live with the possibility of progressive cancer and its difficult treatments. Many who decide to wait become what some physicians refer to as the "walking worried," men who are constantly concerned with their PSA levels. Because aggressive treatment reduces such anxiety, some studies reported that years after surgery, about three quarters of men say they would chose it again, in spite of significant side effects, which include impotence and incontinence in many of them.

Choosing Watchful Waiting

Watchful waiting involves lifestyle change and careful monitoring to see if surgery or radiation becomes necessary. Most patients should have a digital rectal exam and PSA blood test every six to 12 months. If PSA levels rise, more intensive tests are required to determine if the cancer has advanced. Patients should exercise and eat healthy foods. [ See What Dietary Factors Are Associated with Prostate Cancer Risk and Protection?] Symptoms such as weight loss, pain, urinary problems, fatigue, or impotence should be reported to the patient's physician.

Candidates. Watchful waiting is a consideration for the following patients:

Men in their late 70s and older. More aggressive therapies (surgery and radiation) are usually recommended for men in their 50s and younger. The choice for men in their 60s and early 70s is more problematic. The general recommendation at this point is that aggressive therapy is suitable for those who have a life expectancy of more than ten years and who have early and low-grade cancer. At this point the tumor grade is the best guide for determining the risks in choosing watchful waiting.
Elderly men with early-stage (T0 to T2) low-grade tumors.
Men with low to moderate PSA levels.

Because prostate cancer grows so slowly, it is likely that good candidates will die first from causes unrelated to the cancer. There is therefore little potential benefit from surgery or radiation, which both pose a risk for impotence and incontinence.

Choosing Surgery (Radical Prostatectomy)

In men whose cancer is confined to the prostate, surgical resection (radical prostatectomy) offers the potential for cure. Cure rates from initial surgery in men with localized cancer are about 70%, depending on tumor stage, tumor grade, and PSA levels.

Candidates. Radical prostatectomy is a consideration for men who meet all of the following criteria:

In good health and with a life expectancy of 10 years or more. As average life expectancy in men has increased, more older men are becoming candidates for surgery. Complication rates are higher the older a man is, however.
The cancer has not spread beyond the prostate gland.
The cancer is potentially life-threatening. (In general, a life-threatening tumor is indicated by volumes more than 0.2 cc and Gleason grade scores greater than 5.)

The procedure is more likely to cause incontinence (up to 50%) and impotence (as high as 90%) than radiation treatment but has fewer bowel complications. Surgery for prostate cancer may be particularly difficult in men who have had transurethral resection of the prostate (TURP).

Choosing Radiation

Radiation therapy (or radiotherapy) is administered as external-beam radiation or as brachytherapy (radiation implants). It may be used as the sole primary treatment for localized prostate cancer, and has five-year survival rates similar to those of surgery.

Candidates. Radiation is a consideration for men with one or more of the following characteristics:

Being older and, particularly, having other medical problems.
The cancer may have extended beyond the prostate capsule but has not spread to the lymph nodes or further.
Being a good surgical candidates, but having decided against an operation.
risk for impotence (about 50%) and incontinence (less than 10%) is much lower than with surgery, although bowel problems occur in about a third of patients.

Choosing Hormonal Treatments

Hormonal treatment in prostate cancer uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen), particularly testosterone and dihydrotestosterone.

Hormonal Treatments for Local Cancer. Investigators are evaluating a hormonal approach called triple androgen blockade that might prove to be useful for local or locally advanced prostate cancer. It consists of an LH-RH agonist (leuprolide or goserelin), an antiandrogen (flutamide or bicalutamide) and finasteride

Hormonal Treatment After Surgery for High-Risk Patients. Hormonal treatment may be useful after surgery in men who have high-grade tumors or tumors that have invaded the semen-carrying vessels or lymph nodes. Such men have a risk for failure after surgery of 50% to 80%.

Hormonal Therapy Before Radiation. Hormonal drugs combined with or used before radiation therapy (called neoadjuvant therapy) are under investigation and may improve survival rates in moderate- or high-risk groups. Neoadjuvant therapy may be helpful in shrinking enlarged glands to that brachytherapy (radiation implants) can be used.

WHAT ARE THE OPTIONS IF LOCALIZED TREATMENTS FAIL?

Indications of Persistent Cancer after Initial Treatment

Risking PSA Levels. If prostate cancer has been eliminated, PSA levels should drop to 0.5 or less after treatment. A sudden rise or persistently elevated PSA levels after treatment are often indications that prostate cancer persists:

If PSA levels are above 2, then cancer is most likely still present.
If PSA levels are between 0.5 and 2, the situation is less clear. One study indicated that measuring free PSA may help determine the status of the cancer in such patients. An average free PSA of 27% indicated that cancer had been eliminated, while an average of 15% meant that cancer was still present.

Note: It is common for PSA levels to temporarily rise following radiation seed implantation without signaling cancer recurrence.

General Prognosis with Recurrence or Failure

Rising PSA levels do not necessarily mean that the cancer has spread or even that the cancer will recur during a man's lifetime. An actual cure is still possible if the cancer is localized within the prostate. In one study, 64% of patients with rising PSA levels after surgery still had cancer confined to the prostate. Indications of a poorer outlook in this study included the following:

Cancer penetration of the prostate capsule.
Positive surgical margins (microscopic evidence of cancer cells at the very edge of the resected specimen.
Invasion of nearby vessels or lymph nodes.

Still, among the men in the study, after seven years only 3% of patients had actually died of prostate cancer. After fifteen years, only 19% had evidence of recurrence. Other markers for persistent cancer are under investigation. For example blood tests that show low levels of acid phosphatase (ACP) before treatments may predict a higher chance for recurrence-free survival.

Treatment Options

Hormonal Therapy. Hormonal therapy (drugs or surgery that block male hormones) is often the appropriate response to rising PSA levels after treatment failure. Some studies suggest that patients given hormonal drugs may live significantly longer if treatment is started as soon as PSA levels rise, even if no symptoms occur. Other studies indicate there is no increased survival from early treatment, and patients have a better quality of life if therapy is started only after symptoms have occurred.

Chemotherapy. Chemotherapy agents in combination with hormonal agents are being investigated for patients who fail surgery or radiation. (Chemotherapy alone does not appear to offer any benefits.)

Salvage Prostatectomy. Salvage prostatectomy is sometimes performed after unsuccessful radiation treatment if the cancer is still local. The odds of the procedure's success are only 10% to 64%. Many experts recommend against salvage prostatectomy in most cases of radiation failure.

Severe complication rates for salvage prostatectomy are very high: ten times that of men who have not had radiation. Potential complications include:

Need for blood transfusions.
Rectal injury.
Incontinence.
Impotence.

Incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures. [ See What Are the Surgical Treatments for Prostate Cancer?, below.]

Salvage Cryosurgery. Salvage cryosurgery may be effective in certain patients who fail external beam radiotherapy. The best candidates are those with Stage II cancer or less and PSA levels below 10 ng/mL.

Adjuvant and Salvage Radiation. Radiation is proving to be beneficial in patients who still show detectable levels of PSA after surgery (generally 2 ng/ml or less), and may even be useful years after surgery if PSA levels rise. Depending on timing, radiation after treatment failure is referred to as follows:

Adjuvant radiation is radiation therapy performed within 6 months of surgery.
Salvage radiation is radiation therapy more than 6 months after surgery.

One area of controversy is whether to use adjuvant radiation after surgery on patients whose PSA levels are very low or undetectable but who have other test results that indicate that the cancer is likely to spread. For example, analysis of tissue taken during surgery can indicate that the tumor extends outside the prostate capsule. One study reported that when such patients were given adjuvant radiation, they had significantly higher rates of disease-free survival than those who had salvage radiation. Only a minority (20% to 30%) of these patients experienced treatment failure, particularly if they had low to moderate Gleason grade scores. Patients with adverse findings and low PSA have to weigh the potential complications of radiation therapy against the odds of recurrence without it, which are about 20% to 30%.

WHAT ARE THE GUIDELINES FOR TREATING ADVANCED AND METASTASIZED PROSTATE CANCER?

The primary goals of late-stage cancer treatments are to:

Slow cancer progression.
Increase patient comfort.

Treatment options include the following:

Hormonal treatments used to suppress or block androgens (male steroid hormones) are the mainstay treatment for advanced and metastasized cancer (Stage IV).
External beam irradiation is used for late stage patients and is the mainstay for controlling pain caused by metastasis. External-beam radiation used with on-going androgen suppression treatment is being investigated for advanced cancer that has not yet metastasized. [ For more information, see What Are the Radiation Treatments for Prostate Cancer?, below.]
One study has suggested that combinations of certain standard chemotherapy drugs may be useful for patients with advanced prostate cancer who fail hormonal treatments. In this study, after one year, 77% of the patients were alive.
Radical prostatectomy is rarely helpful.

Hormonal Therapies: Blocking Androgens (Male Hormones)

Hormonal treatment is the mainstay for advanced and metastasized prostate cancer. Hormonal therapies (drugs, surgery, or both) are used to suppress or block male steroid hormones, called androgens. Androgens, particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. When prostate cells, both healthy and cancerous, are deprived of androgens, they no longer proliferate and eventually die.

Standard Hormonal Treatments. Surgery to remove the testicles (orchiectomy), hormonal drugs, or both are standard hormonal treatments. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens.

Hormonal Drugs. The primary agents used for suppressing androgens are called luteinizing hormone-releasing hormone (LH-RH) agonists.
Orchiectomy. Orchiectomy is the surgical removal of the testicles. It is the single most effective method of reducing androgen hormones. Orchiectomy plus radical prostatectomy may delay progression in patients with cancers that have spread only to the pelvic lymph nodes. Combining orchiectomy with antiandrogen drug therapy adds a modest benefit. It is an extreme procedure, however, and studies do not indicate that it improves survival rates significantly. The median survival rate after the operation is about 55% over a 40 month period. An estimated 25% of patients survive five years or more. Nevertheless, orchiectomy, although irreversible, may produce fewer adverse effects than hormonal drugs, and interestingly, patients report significantly higher quality of life after orchiectomy than patients who opt for hormonal treatment, particularly total androgen ablation.

Prognosis

Cure is possible in late stage prostate cancer but rare. Even without cure, however, striking subjective or objective responses to treatment occur in most patients.

Unfortunately, in advanced disease, prostate cancer usually returns within 18 months. In such cases, so-called testosterone-independent tumors exist, which are not responsive to antiandrogen therapy. The reason for this is still unknown. One theory is that after cells that are sensitive to male hormones have been blocked, cells that are resistant to androgen are stimulated to grow, and the cancer returns. Some studies have also identified a genetic mutation that signals the cancer cells to grow in response to other hormones even in the absence of androgen.

Researchers are continually searching for drugs to treat relapses and act against these testosterone-independent tumors. Some studies indicate that when tumors recur after antiandrogen treatments, they may actually be sensitive to testosterone. If so, administering androgens at the point of relapse might suppress tumor growth in some situations. More research is needed for this interesting finding.

WHAT ARE THE SURGICAL TREATMENTS FOR PROSTATE CANCER?

Radical Prostatectomy

Radical prostatectomy is the surgical removal of the entire prostate gland along with the seminal vesicles (the vessels that carry semen) and surrounding tissue. The incision can be made in one of the following regions:

Retropubicly (through the abdomen and under the pubic bone, exposing the entire surface of the prostate).
Through the perineum (the skin between the scrotum and the anus).

The gland and other structures are then removed. The operation lasts two to four hours. Advanced surgical techniques called minilaparotomy and laparoscopy are being developed for radical prostatectomy. These techniques use smaller incisions, are less invasive, and may cause fewer complications.

Nerve-Sparing Techniques. Surgical procedures have been refined over the years, and many operations for localized low-grade prostate cancer now spare the nerves that control erection.

A bilateral nerve-sparing procedure saves the nerves on both sides of the sex organs.
A unilateral procedure saves nerves on only one side.

Nerve-sparing techniques can improve quality of life. The ability for sexual intercourse recovers in about a third of patients at three years and nearly 60% at five years after surgery. (Rates vary depending on certain factors, such as the patient's age. The younger the better.) In cases where the tumor is bulky and undifferentiated, nerve-sparing techniques may not be appropriate.

Convalescence. Patients remain hospitalized for up to two weeks. A temporary catheter used to pass urine is kept in place when the patient is sent home and usually removed about three weeks after the operation. The convalescent period at home is about a month. In general, younger patients with early-stage cancers recover fastest and experience the fewest side effects.

Complications from Radical Prostatectomy

Complication rates vary after radical prostatectomy and usually depend on the age of the patient and the experience of the surgeon and medical center. In one center they have ranged from 4% in men in their 40s to 14% in men over 70. Complication rates are 10 times higher in patients who have prostatectomy because of cancer recurrence after radiation treatment.

Complications include the usual risks of any surgery, such as blood clots, heart problems, infection, and bleeding. Complications specific to radical prostatectomy, incontinence, impotence, and contracture of the bladder neck, are discussed below. The mortality rate is very low, about 0.4%.

It should be noted that quality of life usually improves shortly after surgery, and recovery from certain complications, such as incontinence and sexual function, can continue to occur even over years.

Urinary Incontinence. Urinary incontinence is a common complication and a more distressing side effect of surgery for most men than sexual dysfunction. When the urinary catheter is first removed following surgery, nearly all patients lack control of urinary function and will leak urine for at least a few days and sometimes for months. Major medical centers report that continence returns within about 18 months for nearly all men under 70 years old and in the great majority of men older than 70. The average time for return of continence in one center was just 1.5 months.

A number of approaches may help prevent or treat incontinence.

Nerve-sparing techniques can help prevent incontinence, although even in experienced centers, 8% of patients will have some postoperative incontinence, and this rate is much higher (up to 50%) in many community medical centers.
A procedure called endopelvic anterior urethral stitch (EAUS) used with prostatectomy appears to reduce urinary incontinence. In one small study, 75% of selected patients recovered continence in a month. The procedure requires a simple stitch at the front of the urethra.
Kegel exercises, contracting and relaxing the muscles used to shut off the urinary stream, strengthen the muscles on the pelvic floor and are reported to be very beneficial for many men.
If incontinence persists beyond a year, patients may require drug therapy or surgery. Collagen injections into the urethra, bladder neck suspension surgery, or a urinary sphincter implant may be helpful for men who have chronic incontinence. (In one study men had better results with the sphincter implant.) [ For more information, 50, Incontinence.]

Impotence. The first nationally-representative study to evaluate long term outcomes after radical prostatectomy concluded that impotence occurs far more frequently than previously reported. The study included more African American, Hispanic, and young men than previously studied, although there was little difference among ethnic groups. About 40% of the study subjects considered sexual function a moderate to big problem, but over 70% still said they would have the surgery again.

Nerve-sparing procedures are also helpful in reducing impotence as well as incontinence. [See Table Impotence Rates by Procedure].

Impotence Rates by Procedure
Type of Procedure	Sexual Impairment Rate
Bilateral nerve-sparing procedure	56%
Unilateral nerve-sparing procedure	59%
Non-nerve sparing procedure	66%

Researchers are experimenting with a technique that involves harvesting nerve tissue from the patient's calf and grafting it into the pelvis during radical prostatectomy in order to maintain erectile function. It is still too early to determine whether this procedure will be effective, and some experts believe it is unlikely to improve sexual functioning.

A number of treatments for sexual dysfunction are available that may help some men. Sildenafil (Viagra), for example, may help restore potency in an average of 30% of patients. In one study it had an 80% success rate in younger men who were potent before surgery and had bilateral nerve sparing procedures. (The rate was 40% with only unilateral procedure.) It may take nine months or longer to respond to the drug, so men might benefit from alprostadil injections starting right after surgery to preserve elasticity and help prevent scarring. It is unlikely to be effective for men over 55 who had unilateral or no nerve sparing procedures. [ 15, Impotence.]

Even when erectile function is preserved, men may experience other sexual problems:

Erections may not be as rigid as before the operation.
Orgasm and sexual sensation may be altered.
Patients who retain potency may suffer from retrograde ejaculation, also known as dry ejaculation. During ejaculation, semen travels backward into the bladder, causing infertility.
Fecal Incontinence. Radical prostatectomy can also cause fecal incontinence. The risk may actually be higher in men undergoing nerve-sparing procedures.

Contracture of the Bladder Neck. Another common post-surgical complication is contracture of the bladder neck at the point where it has been stitched to the remainder of the urethra. Contracture usually occurs within the first three months after the operation, causing a sharp decrease in urinary stream. The condition can be treated by dilation or surgery on the bladder neck, and rarely recurs.

Pelvic Lymphadenectomy

Pelvic lymphadenectomy is the surgical removal of the pelvic lymph nodes. It is usually performed at the same time as prostatectomy [ see above ]. If the surgeon suspects that cancer has spread beyond the prostate, he will perform the lymphadenectomy as part of the operation. Some surgeons do this procedure as a matter of course when performing prostatectomy, since it has few complications and adds information on the state of the disease. The lymph nodes are removed through an incision in the lower part of the abdomen, using conventional surgery or laparoscopy, a less invasive variation. The nodes are immediately examined. If they show signs of cancer, then metastasis has occurred. In such cases, the operation is usually stopped and the patient is offered radiation or hormone treatments. Experts argue about whether a prostatectomy may still be beneficial. One study found a survival advantage in those who had their prostate removed even when cancer had spread. More research is needed.

Cryosurgery (Cryoablation)

Cryosurgery is an alternative to standard prostatectomy. And, a 2001 study reported that it was as effective as radiation therapy (and perhaps more effective than brachytherapy in patients at medium to high risk.) Survival in the study exceeded 70%, comparable to radiation therapy and brachytherapy. Among patients with localized prostate cancer, the five-year disease-free rate approached 80%. The cryosurgical technologies used in the study were not as good as newer ones now available, so these figures even may understate the technique's performance.

The Procedure. The goal of cryosurgery is destruction of the entire prostate gland and possibly surrounding tissue. Steel probes are inserted through the skin between the anus and the rectum and into the prostate. Liquid nitrogen is pumped through the probes to freeze all prostate cells, both healthy and cancerous. For success, cryosurgery requires a uniformly frozen area. The dead cells are absorbed and eliminated by the body. Patients can leave the hospital in two or three days.

Candidates. Cryosurgery may be considered for patients with the following:

Early stage local cancer.
Cancer that has recurred after radiation treatments.
Large primary tumors that the surgeon wishes to reduce.
Possibly useful for tumors that have spread beyond the prostate if they have not yet reached the lymph nodes.

Strong indicators of treatment failure include:

A history of both hormonal and radiation treatments.
Tumor grades 8 and above.
PSA levels of more than 10 ng/mL.
Complications. Complications are similar to those of standard prostatectomy, but incontinence rates are much lower. In one study, 85% of men who were potent before the procedure reported impotence afterward. Nevertheless 96% reported that they were satisfied with the results. Incontinence and other side effects may be higher in patients who have had previous radiation treatments. Other significant complications include scarring and narrowing of the urethra and fistulas (abnormal passages from internal organs to the skin or between two internal organs).

Orchiectomy

Orchiectomy is surgical removal of the testicles. It is the single most effective method of reducing androgen hormones, but it is considered an extreme procedure. The operation can be done on an outpatient basis, through a tiny incision in the scrotum, and is relatively pain-free.

Sexual Effects. Many men can still achieve erection after orchiectomy, but there is almost always a decline in sexual drive. Men who cannot achieve erection can receive a penile implant. Patients do not experience a reversal of sex characteristics: the voice does not change and body hair is not affected.

Quality of Life. Interestingly, patients who choose this option report significantly higher quality of life afterward than those who opt for hormonal treatment, particularly total androgen ablation. Although the operation impairs sexuality, it causes less fatigue, physical dysfunction, and psychological distress than other treatments for advanced cancer, excluding no treatment at all. These studies, however, did not compare orchiectomy to intermittent hormonal therapy, which may prove to have psychological benefits.

Osteoporosis. Like all androgen deprivation therapies, orchiectomy increases the risk for osteoporosis, a loss of bone density that increases the risk for fracture. In fact, the risk for osteoporosis may be higher with surgery than hormonal drugs.

Investigative Surgical Procedures

Holmium Laser Enucleation, Holmium laser enucleation of the prostate (HoLEP) is an investigative procedure that may prove to be preferable to open prostatectomy.

WHAT ARE THE RADIATION TREATMENTS FOR PROSTATE CANCER?

Two major radiation treatments are now available:

External-beam radiation
Brachytherapy

Advances in both treatments have been generally equivalent in success rates. In some cases, both techniques may be used in high-risk patients.

External-Beam Radiation

In external-beam radiation therapy, a physician focuses a beam of radiation directly on the tumor for 35 three-minute treatments, five times a week, over seven weeks. 3D conformal techniques use computers and a 3-D image of the prostate to provide precise targeting of the tumor using high-dose radiation beams. It allows high doses and poses a lower risk for inflammation. In a 1998 study, the higher-dose conformal therapy significantly improved survival rates compared to lower dose treatment. Men who have had transurethral resection of the prostate (TURP) or have a history of lower urinary tract symptoms may have a better experience with external-beam radiation using 3D conformal techniques.

Brachytherapy

Brachytherapy is an outpatient technique that implants radioactive "seeds" directly into the prostate. Implants can be temporary or permanent. Temporary implants are usually accompanied by external-beam radiation. This procedure requires more skill than external-beam radiation therapy, and even with experienced physicians, the distribution of radioactive seeds is uneven in 15% of cases, increasing the risk for insufficient doses.

Computerized systems are being developed to help oncologists optimize seed placement and allow precise treatment for each patient and higher radiation doses. Eventually, it could improve tumor control, reduce side effects, and cut costs.

It should be noted, that it is common for PSA levels to temporarily rise, or "bounce," following seed implantation without it being a signal for cancer recurrence. This effect can produce anxiety and can interfere with the diagnosis of true recurrence.

Candidates. Studies are indicating the brachytherapy is useful for select patients, specifically those with prostate volumes less than 60 mL and who have early-stage prostate cancer (T1 or T2 tumors, a Gleason grade lower than 7, and PSA levels below 10 ng/mL). It may be beneficial in patients with inflammatory bowel disease or with cancer close to the bowel. Poor candidates for brachytherapy include men who have had TURP and patients with advanced cancer, high-grade tumors, or very enlarged prostate glands.

Complications from Radiation

The side effects of radiation therapy include most of those of surgery, but the risks for impotence and incontinence are considerably lower. A 2000 study concluded that adjuvant radiation therapy (given right after surgery) in moderate doses does not increase the risk for long-term urinary incontinence or sexual dysfunction beyond that of surgery alone.

Gastrointestinal Complications. Complications in the gastrointestinal are common. Short-term effects include:

Loss of appetite.
Nausea.
Diarrhea is a very common side effect and can last for the duration of therapy. It is usually treated with Lomotil. A few patients have diarrhea flare-ups for years afterwards. Less than 1% suffer more serious intestinal problems.
There is potential for injury to the rectum with brachytherapy. Ulcers in the rectum occur in over 10% of patients, but the risk decreases with greater experience in the technique.

Urinary Problems. The risk for incontinence is about 7% to 20%. Patients treated with radiation may experience a painful, but usually temporary, urinary tract inflammation. About 10% to 15% of patients develop a long-term urgent and frequent need to void their bladder. Brachytherapy carries a lower risk for urinary incontinence.

Scarring and narrowing of the urinary tract (stricture) may occur, particularly in men who had TURP performed within a short time before radiation treatment. In such men, radiation treatments should be delayed by four to six weeks. If the prostate has been injured or damaged or the bladder is easily irritated, side effects with brachytherapy may actually be worse than with other procedures.

Impotence. Risks for impotence are around 40% in men who have brachytherapy and are between 60% and 70% or higher with external beam radiation. Although brachytherapy may pose less of a risk for impotence than external-beam radiation or surgery, one study reported a high long-term rate of impotence (53%) after five years. Sildenafil (Viagra) may be effective for 70% of men experiencing impotence following radiation therapy for local prostate cancer. Other treatments may also be useful. [ See also Report #15, Impotence.] A 2000 study suggested that the dose of radiation received by the bulb of the penis correlates with risk of impotence. If this is confirmed by further study, carefully designed radiation may improve current rates.

Experimental Radiation or Other Nonsurgical Procedures

Investigative Radiation Treatments. Investigators are also testing radiation treatments that use a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard proton radiation therapy.

High-Intensity Focused Ultrasound (HIFU.). Studies are reporting promise with an intensive ultrasound procedure called transrectal high-intensity focused ultrasound (HIFU). It allows for very precise minimally-invasive removal of tissue in local prostate cancers. It may eventually prove to be an alternative to radiation therapy. More research, with long-term follow up, is needed.

Thermoradiotherapy. Thermoradiotherapy is a procedure that combines heat and conformal radiation. A 2000 study reported that it is a well-tolerated treatment for prostate cancer. The researchers reported a significant drop in PSA, but more research is needed.

Implanted Magnetic Rods An interesting and unique procedure implants very small rods that heat up when exposed to a magnetic field and destroy surrounding tissue. The rods are permanent, so therapy can be repeated non-invasively if the patient's PSA levels rise. The US Food and Drug Administration has approved a clinical study at the University of California San Francisco, treating patients who have recurring cancer after undergoing radiation therapy.

WHAT ARE THE HORMONAL DRUG TREATMENTS FOR PROSTATE CANCER?

Androgen Suppression Drug Therapy Guidelines

Hormonal therapy, either drugs or orchiectomy (surgical removal of the testicles), is used under the following circumstances:

Hormone therapy is used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels).
Hormone therapy is used for treating advanced or metastasized prostate cancer.

Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose drug therapy to block androgens. It should be noted that hormonal therapy is not a cure. Further, between 20% and 30% of patients do not respond to hormonal treatment; success rates given in studies then are not based on the total cancer patient population.

LH-RH Agonists

The primary agents used for suppressing androgens are called luteinizing hormone-releasing hormones (LH-RH) agonists. They include:

Leuprolide (Lupron, Leuprogel). Studies report that disease progression is prevented in 72% of men taking daily leuprolide and up to 89% of those taking monthly injections. Certain men, however, may not respond to injections. Drug delivery using implants is under investigation.
Goserelin (Zoladex). Partial responses of 60% to 80% have been reported.
Buserelin.

LH-RH agents block the pituitary gland from producing hormones that stimulate testosterone production. Patients must have injections of LH-RH agonists for the rest of their lives.

Testosterone and PSA Surges. Treatment with LH-RH agonists produces a testosterone surge in the first week, which may actually intensify symptoms. After this phase, testosterone levels drop to near zero. Leuprogel, a newer leuprolide, may pose a lower risk for this effect. Researchers are investigating other drugs, such as GnRH antagonists, that do not produce this surge. [ See below. ]

LH-RH agonists can also cause PSA levels to rise temporarily. A 2000 study suggested that administering flutamide, a drug known as an antiandrogen, for two weeks prior to LH-RH agonists may not only prevent PSA surge but also induce early declines in PSA levels.

Side Effects. Side effects include hot flashes and occasionally nipple and breast tenderness.

Antiandrogens

Antiandrogens are powerful agents produced in the adrenal gland. They are used alone or in maximal androgen blockage (MAB), in which they are combined with LH-RH agonists or orchiectomy to completely block androgen hormones. Antiandrogens are either steroidal or nonsteroidal.

Nonsteroidal Antiandrogens. The nonsteroidal drugs are as follows:

Flutamide (Eulexin, Drogenil). Flutamide has produced extended response in some patients. Interestingly, studies report that simple withdrawal produced a PSA decrease in about 20% of patients, which lasted between 3.5 and 5 months. Side effects reported with flutamide include diarrhea and liver damage, which has been fatal in rare cases; liver function must be monitored closely.
Nilutamide (Nilandron). Nilutamide is associated with reversible interstitial pneumonitis, nausea, alcohol intolerance, and visual disturbances.
Bicalutamide (Casodex). Bicalutamide may be as effective and have fewer severe side effects, including loss of sexual interest and osteoporosis, than other antiandrogens. This agent is proving to be an alternative to maximal androgen blockage (MAB) using goserelin plus flutamide or orchiectomy. In a comparison study with MAB, survival rates were similar. The bicalutamide group reported more breast swelling but the MAB group had significantly worse diarrhea and hot flashes. Both groups reported impaired sexual function. Physical capacity increased in those taking bicalutamide and decreased in the MAB group. In a comparison study with orchiectomy, patients taking bicalutamide had more sexual interest and physical capacity, and preliminary data indicates that bicalutamide does not deplete bone mineral density.

Steroidal Antiandrogens. The steroidal antiandrogens act like female hormones and include the following:

Megestrol Acetate. (Megestrol acetate suppresses androgen production, but incompletely, and is generally not used as initial therapy.)
Cyproterone acetate. (Cyproterone combined with estrogen may prevent the testosterone surge that occurs with LH-RH agonists.)

Gonadotropin Releasing Hormone (GnRH) Antagonists

Gonadotropin releasing hormone (GnRH) antagonists are relatively recent agents. Those studied include abarelix and histrelin. (GnRH is another name for luteinizing hormone-releasing hormones (LH-RH). Drugs known as GnRH antagonists have two advantages over LH-RH agonists:

They do not cause the same testosterone surge that can temporarily worsen cancer symptoms.
They seem to reduce testosterone levels more quickly.

In one study, histrelin was administered as an implant and was effective for up to 30 months. This offers an advantage over existing drugs, which must be administered at one to three -month intervals.

Estrogens

Estrogens, usually diethylstilbestrol (DES), may also be used. These female hormones may exacerbate heart conditions in high doses and their use has declined. Other estrogens, such as fosfestrole, may prove to be effective without posing such high risks. An estrogen agent, estramustine phosphate, which is also used in chemotherapy, is showing promise.

Drug Treatments for Maximal Androgen Blockage (MAB)

Unfortunately, even after using standard hormonal agents, residual testosterone is usually present. In such cases, physicians may try drugs or techniques to produce a complete shut-down of all male hormones. This approach, known as maximal androgen blockage (MAB), uses LH-RH agonists or orchiectomy combined with other agents known as antiandrogens. MAB, however, has considerable adverse effects on quality of life, and studies suggest that survival benefits are very modest over androgen suppression with single agents or orchiectomy. (One 2000 study suggested that taking MAB longer than 120 days may improve survival times.)

Intermittent Androgen Suppression. Oddly, stopping antiandrogens sometimes causes PSA levels to drop again, a phenomenon called the antiandrogen withdrawal syndrome. This has led to investigation of therapy that uses intermittent androgen suppression, which involves alternating cycles of therapy and rest. First, antiandrogen drugs are given for at least six months until PSA levels are at their lowest and remain there. The drugs are then stopped until PSA levels rise again to greater than 10 ng/ml, at which point treatment resumes. This cyclic therapy appears to delay tumor progression, and in any case, it offers a drug-free period in which the patients experience renewed sexual function and a greater sense of well-being.

Sequential Androgen Blockage. Sequential androgen blockage, like intermittent androgen suppression, is designed to effectively reduce the effects of testosterone while offering the patient some relief from side effects. It uses drugs known as 5 alpha-reductase inhibitors to block conversion of testosterone to dihydrotestosterone along with an antiandrogen to mop up any residual male hormones. This treatment allows some testosterone to remain in circulation and helps prevent some of the distressing side effects of total androgen ablation.

Complications of Androgen Deprivation

Men often experience fatigue, loss of energy, and emotional distress. Hormonal therapy may significantly impair quality of life, particularly in men who had no symptoms beforehand and whose cancer has not metastasized. Common side effects of androgen suppression drugs include the following:

Osteoporosis, the loss of bone density. This risk is higher with orchiectomy than with androgen suppressants. It does not occur with all androgen suppressants. The use of estrogens may actually be bone protective.
Diarrhea
Loss of muscle mass
Psychological disturbances
Fatigue
Loss of sexual drive and sexual dysfunction
Swelling of the breasts (gynecomastia)
Nausea and vomiting
Hair loss
Anemia

Needless to say, these side effects can cause severe emotional problems.

Secondary Therapies for Manipulating Hormones

For relapsing cancers after androgen suppression fails, researchers are investigating the use of other therapies that affect hormonal triggers of prostate cancer.

Ketoconazole. Ketoconazole, usually used to fight fungal infections, is a nonhormonal drug that inhibits an enzyme that stimulates production of testosterone. It is effective in high doses but can have severe gastrointestinal effects, mainly nausea and anorexia. Long term use can result in impotence, itchy skin, nail changes, and suppression of stress hormones. One center reported a consistent PSA response in more than 60% of patients who had failed other androgen suppressing treatments.

Aromatase Blockers. Drugs, such as aminoglutethimide (Cytadren) that block aromatase, an enzyme important in estrogen production, are being studied. Because the female hormone estrogen plays such a major role in the development of breast cancer, some experts postulate that blocking the small amount of estrogen found in men may also affect prostate cancer. Side effects include drowsiness and skin rash.

WHAT ARE NONHORMONAL DRUGS USED FOR PROSTATE CANCER?

Chemotherapy

Chemotherapy for prostate cancer improves symptoms but standard agents have not improved survival rates. A number of drugs are being investigated, both alone and in combinations, for cancer that is unresponsive to hormone treatments. These drugs include vinblastine, mitoxantrone, vinorelbine, adriamycin, mitoxantrone, and estramustine (which combines estrogen with nitrogen mustard and acts on prostate cells). Amsacrine and etoposide, which break down DNA, may prove to be effective for men with certain inherited forms of prostate cancer. Unfortunately, studies to date are reporting toxicities and lack of effect with some of these agents. A study of vinorelbine had more encouraging results; the drug was shown to be safe and provided relief from symptoms, especially bone pain. Paclitaxel and docetaxel, drugs used in gynecologic cancers, are also showing promise.

Corticosteroids

Corticosteroids, such as prednisone, are important for reducing pain and improving quality of life. Some experts believe they should be the first choice for progressive prostate cancer that is resistant to hormonal treatments. Corticosteroids may be particularly effective in relieving pain and delay disease progression when used in combination with chemotherapy drugs, particularly mitoxantrone. There is evidence that corticosteroids can reduce PSA levels and boost survival in some patients.

Immunotherapy

Immunotherapy for cancer uses agents that enhance the power of the patient's own immune system to fight cancer cells.

Vaccines. One technique employs genetically-designed vaccines that inject factors into prostate cancer cells to serve as antigens so that the immune system is tricked into attacking the real cancer cells. A number of vaccines (eg, Provenge, Gvaz, JBT 1001) are in clinical trials. Researchers have identified an antigen that may be unique to prostate cancer cells and so a potential very effective target for a vaccine.

Monoclonal Antibodies. Monoclonal antibodies are genetically designed immune factors that target and attack specific antigens and are being tested with prostate cancer cells.

Bisphosphonates

Bisphosphonates are proving to be very helpful for reducing bone pain in metastasized cancers. These drugs actually help inhibit prostate cancer cell growth in the bone.

Other Investigative Agents

A number of non-hormonal drugs are under investigation.

Potent Nonsteroidal Anti-inflammatory Drugs. COX-2 inhibitors and potent NSAIDs, such as exisulind or sulindac (Clinoril), are being investigated for treating and delaying recurrence of prostate cancer after surgery.

Vitamin-D Derived Treatments. Some studies are reporting that vitamin-D derived agents, such as calcitriol, may eventually be beneficial for prostate cancer patients, particularly in combination with other chemotherapies. Liarozole blocks the break down of retinoid acid (a vitamin A derivative important in maintaining normal cell growth and structure) and is showing promise for reducing PSA levels and improving symptoms in early trials.

Angiogenesis Inhibitors. Thalidomide, and AE-941 (Neovastat) are investigative agents that inhibit angiogenesis, the formation of new blood vessels that are critical for spreading cancer. It is still too early to determine whether these therapies will be effective.

Matrix Metalloproteinase Inhibitors. Drugs are being tested in clinical trials that inhibit matrix metalloproteinase, which are enzymes that may degrade cell structure allowing cancers to grow and metastasize.

Doxazosin. Doxazosin (Cardura), a drug commonly used to treat benign prostatic hyperplasia, has been shown to kill prostate cancer cells in lab experiments. The effects are amplified when doxazosin is combined with adriamycin or etoposide, chemotherapy drugs. More research is needed to determine if this effect has significance for patients.

PC-SPES. An extract from eight Chinese herbs referred to as PC-SPES is showing promise in reducing PSA levels by up to 80% in some men. Side effects include breast swelling, leg cramps, nausea and vomiting, and blood clots due to the estrogenic activity of these herbs.

Quercetin. Q uercetin is a flavonoid compound found in apples, onions, black and green tea, red wine, green leafy vegetables, beans, and citrus fruits. It may have specific actions that block androgen activity in prostate cancer cells, making it a good research subject.

Atrasentan. Atrasentan shows promise in reducing bone loss and delaying progression of prostate cancer in men with advanced disease that no longer responds to hormone therapy. Side effects are relatively mild.

WHERE ELSE CAN HELP BE OBTAINED FOR PROSTATE CANCER?

National Cancer Institute Call (800-4-CANCER) (800-422-6237) during working hours. Deaf and hard of hearing callers with TTY equipment may call (800-332-8615) Call CancerFax at 800-624-2511 or 301-402-5874 from your touch-tone phone or from the telephone on a fax machine (the machine must be set to touch-tone dialing). or on the Internet (http://www.nci.nih.gov/)

American Cancer Society, 1599 Clifton Road, NE, Atlanta, GA 30329-4251 Call (800-ACS-2345) or (404-320-3333) or on the Internet (http://www.cancer.org)

American Society of Clinical Oncology, 1900 Duke Street, Suite 200, Alexandria, VA 22314 Call (703) 299-0150 or on the Internet (http://www.asco.org)

National Prostate Cancer Coalition, 1156 15th St., NW, Washington, DC 20005. Call (888-245-9455) or on the Internet (http://www.4npcc.org)

Cancer Care, Inc., 275 7th Avenue, New York, NY 10001, Call (800-813-HOPE) or (212-712-8080)or on the Internet (http://www.cancercare.org/index.asp)

American Foundation for Urologic Disease , 1128 North Charles Street, Baltimore, MD 21201. Call (800-242-2383) or (410 468-1800)or on the Internet (http://www.afud.org/)

Digital Urology Journal 300 Longwood Avenue, Hunnewell 3, Boston, Massachusetts 02115.
An online journal with research articles on urologic problems is located at (http://www.duj.com/)

National Association for Continence (NAFC), Box 8310, Spartanburg, SC 29305-8310 Call (800-BLADDER) or on the Internet (http://www.nafc.org/)
Offers free literature. Paid membership includes a resource guide, a quarterly newsletter, the Resource Guide (a very comprehensive directory of products and services for the incontinent), and referrals to physicians who specialize in continence. Acts as an advocate for the incontinent with governmental agencies, insurance companies, and health organizations.

The Simon Foundation for Continence, Box 835-F, Wilmette, IL 60091 Call (800-23-SIMON)or on the Internet (http://www.simonfoundation.org)

American Institute for Cancer Research (AICR), 1759 R Street N.W., Washington, D.C. 20009. Call 1-800-843-8114 or (202) 328-7744 in Washington, D.C. Internet source for dietary recommendations: (http://www.aicr.org)

For Internet Users

Listing of clinical trials (http://www.centerwatch.com/studies/listing.htm)

Journal of Clinical Oncology (http://www.jco.org/)

National Comprehensive Cancer Network (http://www.nccn.org/)

PSA Rising Magazine (http://www.psa-rising.com/)

Useful site for learning about cryosurgery (http://members.aol.com/dtkn21/endo/tcap_info.html)

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