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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, see Report #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