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In This Report

•	Highlights
•	Introduction
•	Prognosis
•	Risk Factors
•	Symptoms
•	Conditions with Similar Sym...
•	Screening and Diagnosis
•	Tests to Determine Severity...
•	Staging and Grading
•	Treatment Options by Stagin...
•	Treatment for Localized Pro...
•	Surgery
•	Radiation Treatments
•	Options if Treatments Fail...
•	Other Treatments
•	Resources

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Prostate Cancer

Highlights

New Treatment

Docetaxel (Taxotere) injection combined with prednisone has been approved for treatment of patients with advanced metastatic prostate cancer cancer. Other docetaxel-based combination chemotherapy regimens are being investigated for hormone-refractory prostate cancer.

Research Findings

• Hormone treatment. For men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments may result in greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; this new research suggests that a shorter regimen may be equally beneficial for some patients, and may help reduce side effects associated with androgen-suppressing drugs.
• Brachytherapy. Implantation of radioactive seeds may be sufficient for men with lower-risk forms of prostate cancer. Additional types of treatment (radiation, hormone therapy) may be needed only for more aggressive cancer.
• Salvage Radiation. Salvage radiation could be more beneficial than previously thought, even for men with aggressive prostate cancer. According to a study of men who had undergone radical prostatectomy followed by radiation treatment for cancer recurrence, patients with lower Gleason scores and lower PSA levels benefited the most from salvage radiation. Salvage radiation also help some men with higher-grade disease delay metastasis.
• Red wine. Increasing consumption of red wine may help reduce the risk of prostate cancer. Researchers speculate that the flavonoids in red wine may inhibit tumor cell growth.

Continuing Investigation

The National Cancer Institute is conducting a large-scale clinical trial of more than 35,000 men to investigate whether selenium, vitamin E, or a combination of these two dietary supplements can help to prevent prostate cancer.

Introduction

Prostate cancer is a malignant tumor that arises in the prostate gland. 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 is an organ that surrounds the urinary urethra in men. It secretes fluid which mixes with sperm to make semen.

Hormones and Prostate Cancer

Male hormones (androgens) play major roles in the development of prostate cancer. Some research, for example, reported 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. Nevertheless, researchers have not yet fully clarified the specific mechanisms that may be important in the development of this disease. Most likely, genetic mutations affecting androgens trigger the process. Certain growth hormones, such as insulin-like growth factor-I, are unrelated to testosterone and may increase the risk for prostate cancer.

Click the icon to see an image of the male reproductive anatomy.

Prognosis

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 32,200 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%.

Treatment of prostate cancer varies depending on the stage of the cancer (i.e., spread) and may include surgical removal, radiation, chemotherapy, hormonal manipulation or a combination of these treatments.

Prognosis for Early Stage Disease

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 can be as high as 98% in some cases.

Click the icon to see an image of the pelvic lymph nodes.

Prognosis in Late Stage Disease

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.

Risk Factors

The major risk factors for prostate cancer include genetic, dietary, and environmental factors that effect male hormones (androgens) and make a man more susceptible to this cancer.

Age

Prostate cancer is the most common cancer in the US after skin cancers. It is also the second leading cause of cancer deaths among men. More than 220,000 new cases are reported each year, and, as the population ages, this number is expected to significantly increase. Prostate cancer occurs almost exclusively in men over the age of 40 and most often after the age of 50. It is estimated that by age 70, about 65% of men have at least microscopic evidence of prostate cancers. Fortunately, the cancer is often very slow growing and older men with the cancer nearly always die of something else.

Family History and Genetic Factors

Some evidence has suggested that heredity may play a role in prostate cancers. Men with a family history of the disease have a higher risk of developing prostate cancer. Having one family member with prostate cancer doubles a man's own risk and having three family members poses an 11-fold risk for the disease.

A number of genes are under investigation but the genetic mechanism appears to be very complex. Some early-onset cases of prostate cancer associated with specific inherited genes have been identified, but they account for a small percentage of cases.

A gene is a short segment of DNA which is interpreted by the body as a plan or template for building a specific protein. Genes reside within long strands of DNA which in turn make up the chromosomes.

Ethnicity

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 more lethal among African Americans. Of note, men who live in Asia have lower risks for prostate cancer, but their risk increases if they move to North America. Thus, there are unknown environmental or dietary factors that can alter a man's underlying genetic risk of developing this disease.

Socioeconomic Issues. The higher mortality rates in African American men may be partly due to socioeconomic factors, such as lack of insurance, irregular screening and a late diagnosis, and unequal access to health care. 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.

Dietary Factors.. Dietary factors may play some small role in the higher risk in African men. This is suggested by the fact that prostate cancer is rare in many parts of Africa.

Biologic Factors. Some evidence suggests that African American and Asian men have certain genetic factors that may affect male hormones differently and so help account for the higher risk in the first group and the lower risk in the second. Other research reports 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.) Still, evidence is weak on such genetic and biologic differences and more research is needed.

Higher PSA Levels. African American men also tend to have higher PSA levels than Caucasians. They are overdiagnosed with prostate cancer by 37% compared to 15% in Caucasians using PSA screening tests.

High Exposure to Chemicals and Electromagnetic Fields

Chemicals. The relationship between prostate cancer and chemical exposure is controversial. 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.

Infection and Inflammation

Specific genetic factors that affect the body's response to viruses have also been associated with inherited prostate cancer cases. Some association has been seen between prostate cancer and bacterial or viral infections, such as herpesvirus, human papillomavirus, and cytomegalovirus. Although some of these agents are sexually transmitted, the association with sexual activity is still unclear. One theory suggests that in men with such genetic susceptibilities, any sexually transmitted infection can produce a chronic inflammatory condition in the prostate, which, over time, can initiate cancerous changes. Such beliefs are supported by a possible lower risk in men who take nonsteroidal anti-inflammatory drugs (NSAIDs). More research is needed.

Other Factors Associated with Prostate Cancer

Nonmelanoma Skin Cancers and Sunlight. One study reported that patients with prostate cancer and a history of nonmelanoma skin may have a higher risk for a poorer outlook. Such skin cancers are highly associated with exposure to sunlight. It should be noted, however, that 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.

Vasectomy. Because testosterone levels remain higher for a longer period in men who had vasectomy, experts have postulated that such men have a greater chance for developing the cancer. A 2002 meta-analysis of 22 studies indicated a higher risk with vasectomy, but most recent studies are reporting no higher danger.A rigorous 2002 study from New Zealand, for example, which has the highest vasectomy rates in the world, found no increased risk of prostate cancer from the procedure, even 25 years after the operation.A 2002 study in California, in fact, reported a lower risk for prostate cancer in men who had had vasectomies. It is possible that the higher rates reported in the early studies may simply be due to earlier prostate screening in men who have had vasectomies. Indeed one study reported that about 25% of physicians screened men with vasectomies earlier for prostate cancer than those without the operation. [For more information, see Well-Connected Report #37 Vasectomy.]

Click the icon to see an illustrated series detailing a vasectomy.

Click the icon to see an animation on vasectomy.

Dietary Factors

A Western lifestyle is associated with prostate cancer, so obesity, high-meat intake, and dietary fats have been intensively studied. Results have been inconsistent, however. Certain factors, such as carcinogenic compounds in well-cooked meat or high-calorie intake, may help explain the associations between such dietary factors and cancer risk.

Obesity and High-Calorie Intake. A 2001 study reported that obesity was associated with a modest increase in prostate cancer mortality, although not with the risk for prostate cancer itself. Some evidence suggests that it is a high-calorie intake rather than obesity or fat intake increases the risk for prostate cancer.

Click the icon to see an image on different types of weight gain.

Fats. Some, but not all, studies have found some association between high fat-intake and prostate cancer. This association may be explained by other suspected dietary factors for prostate cancer, such high-calorie diet, high meat intake, and calcium (found in dairy products), which are all also associated with fat intake. The effects of specific fatty acids (compounds that make up fats) may also help clarify the role of fats in prostate cancer. The omega-3 fatty acids in fish (EPA and DHA) and the omega-3 fatty acids found in certain vegetables (ALA) can all protect the heart, but they may have different effects on the prostate.

• Marine Omega-3 Fatty Acids. Research indicates that docosahexanoic acid (DHA) and eicosapentaneoic acid (EPA), the omega-3 fatty acids found in fish, may be protective against prostate cancer. Some studies have reported a lower risk for prostate cancer in men who ate fish frequently (two or more times a week).
• Alpha-Linolenic Acid. On the other hand, some research has indicated that alpha-linolenic acid (ALA), the omega-3 fatty acid found in certain plants and nuts (e.g., flaxseed, canola, walnuts), may increase the risk of prostate cancer.

Meat and High-Temperature Cooking. Some evidence suggests that a high intake of red meat raises the risk for prostate cancer (also possibly colon cancer). Because red meat is often in fat, such findings may explain the inconsistencies found in studies that simply look at fat content as a risk for prostate cancer. Perhaps of more importance, high-temperature cooking (grilling, broiling, or pan-frying) of meat or poultry has been specifically associated with increased risk for cancer in some studies, Over-cooking meat increases the amount of compounds called heterocyclic amines, which has been associated with cancerous changes in general and prostate cancer in particular, at least in some studies. Cooking meats in liquid does not appear to increase these compounds. As with all dietary studies, some have observed no association between high intake of well-cooked meat and prostate cancer. Thus, this is a controversial area that requires more research

Vegetarian Diet. Small studies suggest that a vegetarian diet may be protective. Specific foods may be especially helpful in reducing the risk prostate cancer:

• Whole grain cereals, seeds, and nuts have been associated with a lower risk for prostate cancer. 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 also contain selenium, a rare element that may have some protective properties.
• Many studies have reported a significantly lower risk for prostate cancer with high intake of cooked tomatoes, which are high in a beneficial plant chemical called lycopene. (Some studies have not reported such protection, although intake may have been too low.)
• Soy may also be protective, which may partially explain the low rate of prostate cancer observed in Japanese men and vegetarians (who typically use soy as a protein replacement). Theoretically soy, which is a rich source of an estrogen-like plant compound, may inhibit hormones that promote prostate cancer. Laboratory studies are mixed on such effects, however. Bowman-Birk inhibitor is a soybean-derived product that is being investigated for its effects on prostate health and possible prevention of prostate cancer. A 2001 trial of a concentrated form was associated with a decrease in serum PSA levels and in prostate volume. There is some concern, however, that such agents may increase the risk for pancreatic cancer.
• Cruciferous vegetables (e.g., cauliflower and broccoli) have cancer-fighting chemicals.
• Boron-rich foods (e.g., nuts, red grapes, avocados, and dried fruits) may also be protective.
• Green tea. Scientists have speculated that the antioxidants contained in green tea may help to inhibit prostate cancer growth. Investigators are researching the effects of both green tea and green tea extract supplements, but results to date have been inconclusive.

Dairy Products, Calcium, and Vitamin D. Studies have reported an association between consuming large amounts of dairy products and a modestly increased risk for prostate cancer. (Moderate intake has not been associated with a higher risk.) That is some evidence that calcium (contained in dairy products) may increase the risk for prostate cancer by reducing levels of the most active form of vitamin D (1,25 dihydroxyvitamin D), which may 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. And, it should be noted that evidence strongly suggests that calcium reduces the risk for colon cancer.

Getting enough calcium to keep bones from thinning throughout a person's life may be made more difficult if that person has lactose intolerance or another reason, such as a tendency toward kidney stones, for avoiding calcium-rich food sources. Calcium deficiency also effects the heart and circulatory system, as well as the secretion of essential hormones. There are many ways to supplement calcium, including a growing number of fortified foods.

Click the icon to see an image of the benefits of vitamin D.

Click the icon to see an image of the sources of vitamin D.

Vitamins and Mineral Supplements

Vitamin E. Vitamin E is being investigated for possible protection against prostate cancer. To date, four trials have found that vitamin E may provide some reduction in risk for past and current smokers and for men with vitamin E deficiencies. Of concern was an association in one study of a higher risk for aggressive prostate cancer in nonsmoking men who took high doses of vitamin E (100 IU or greater).

Click the icon to see an image of the benefits of vitamin E.

Click the icon to see an image of the sources of vitamin E.

Selenium. Selenium is a trace mineral found in Brazil nuts, most red meats, poultry, shellfish, and dark mushrooms. In laboratory studies, selenium has acted directly on prostate cancer cells, stimulating cell death and inhibiting growth. In one 2003 study, selenium levels were measured in toenail clippings. Those with the highest levels had the lowest risk for prostate cancer. The findings were particularly pronounced in ex-smokers. Other studies on significant protection from selenium supplements against prostate cancer, however, have been weak. It is possible that supplements may benefit only those who have selenium deficiencies.

The National Cancer Institute is conducting a large-scale clinical trial of more than 35,000 men to investigate whether selenium, vitamin E, or a combination of these two dietary supplements can help to prevent prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the largest prostate cancer prevention trial ever initiated.

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. Some laboratory studies suggest that zinc might inhibit activation of prostate cancer cells. A 2003 study, however, reported that men taking zinc supplements in high doses (100 mg) had a higher risk for advanced prostate cancer. Of note, such men also took higher levels of calcium, iron, and other supplements that might have biased these results. More research is needed to determine the role of zinc on prostate health.

Alcohol

Alcohol consumption does not appear to be associated with increased prostate cancer risk. A recent study, however, suggested a linear trend between red wine consumption and reduced risk of prostate cancer. In a study of over 1400 newly diagnosed middle-aged prostate cancer patients and matched controls, researchers found that each additional glass of red wine consumed per week reduced the relative risk of prostate cancer by 6%. Researchers theorize that the flavonoids contained in red wine may inhibit tumor cell growth. More research is needed to confirm these results.

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 is an important component of any health-protective program.

Finasteride (Proscar)

Finasteride (Proscar) blocks an enzyme that converts testosterone to dehydroepiandrosterone (DHEA), the form of the male hormone that stimulates the prostate. The agent is used to shrink the prostate in men with benign prostatic hyperplasia. It is, therefore, being investigated for prevention of prostate cancer. A large 2003 study suggested that taking it may reduce the risk for prostate cancer by 25%. (On the negative side, the drug can impair sexual function.) The study had some problems, however. For example, in the placebo group, the rate of prostate cancer was much higher than in other studies. Comparing the lower risk from Proscar to other studies, then, would make the reduction less significant. Also when men taking Proscar did develop prostate cancer, the tumor cells tended to be aggressive types. Experts are investigating whether this observation has any significance. One possibility is that the drug actually stimulates high-grade cancer cells. Until more is known, experts do not recommend this agent for prevention.

Sexual Activity

Frequent ejaculations from masturbation or sexual activity has been associated with a lower risk for prostate cancer. Some experts speculate that certain carcinogens may be concentrated in prostate fluid, so that frequent ejaculation helps eliminate them. Of note, risky sexual activity, such as with multiple partners, increases the risk for sexually transmitted disease, which in turn may increase the risk for prostate cancer.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

There is some evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) 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). Many other NSAIDs, such as sulindac (Clinoril), are available only by prescription and are being studied for protection. Newer agents, such as celecoxib (Celebrex), rofecoxib (Vioxx), valdecoxib (Bextra), and meloxicam (Mobic) may warrant specific investigation. A 2002 study reported a 50% reduction in the risk for prostate cancer in men over 60 who took a daily NSAID, although conclusive evidence is still needed.

Symptoms

Prostate cancer usually causes no symptoms in the early stages. As the malignancy spreads, it may constrict the urethra and cause urinary problems.

Urine flows from the kidney through the ureters into the urinary bladder where itis temporarily stored. As the bladder becomes distended with urine, nerve impulses from the bladder signal the brain that it is full which gives the individual the urge to void. By voluntarily relaxing the sphincter muscle around the urethra, the bladder can be emptied of urine. Urine then flows out through the urethra.

Later Stage Urinary Symptoms

Later-stage urinary 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.

Late Stage General Symptoms

Significant pain in one or more bones may herald the occurrence of 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.

Conditions with Similar Symptoms

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 Well-Connected Report #71 Benign Prostatic Hyperplasia.]

Benign prostatic hypertrophy (BPH) is a non-cancerous enlargement of the prostate gland, commonly found in men over the age of 50.

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 10-year study found no higher risk for prostate cancer in men with BPH.

Click the icon to see an animation about benign prostatic hypertrophy.

Prostatitis

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

Screening and Diagnosis

The PSA blood test is widely available for screening men for prostate cancer. However, there is great uncertainty over whether regular screening has major benefits for most men. The most recent guidelines from the U.S. Preventive Services Task Force report that there is no conclusive evidence that routine prostate screening saves lives. Indeed, it may lead to invasive testing and treatments for many men who, considering the slow growth of the cancer, might derive no benefits from them. It is a difficult subject and men must discuss all aspects carefully with their physician.

Standard Screening Tests for Early Detection. Currently, two standard tests are used for early detection of prostate cancer:

• Digital rectal examination (DRE). With the DRE, a physician palpates the prostate in order to feel lumps or masses.
• PSA test. The PSA blood test measures the level of a protein called prostate-specific antigen. It is able to detect early prostate cancer, although it has limitations.

If the digital rectal examination indicates the possible 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.

Candidates for Annual Screening. Until major studies report on the survival benefits of prostate screening, expert groups current recommend the following:

• Men aged 50 to 70 should be offered annual screening. (Some experts believe that men whose PSA levels are under 1.0 and possibly under 2.0 may safely be screened only every two years thereafter.)
• Men with a family history of prostate cancer and all African-American men should consider annual screening at about age 40.

The best age to start annual screening is under debate. Some experts advocate performing a first PSA test in all men aged 40 and then monitoring anyone whose PSA levels are over 0.60 ng/mL. They argue that such men are at high risk for developing prostate cancer within 25 years.

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.

Prostate Cancer is the most common cancer in men in the United States. Prostate cancer forms in the prostate gland, and can sometimes be felt on digital rectal examination. This is one of the purposes of the digital rectal exam. The presence of cancer in

PSA Test

PSA is a protein produced in the prostate gland that keeps semen in liquid form. Prostate cancer cells appear to produce this protein in elevated quantities. Measuring PSA levels, then, increases the chance for detecting the presence of cancer when it is microscopic. There are many unresolved questions surrounding PSA testing. The test is not accurate enough to either completely rule out or confirm the presence of cancer. Relying too much on the test may lead to unnecessary biopsies. Not relying on it enough may miss cancers. In fact, it is still unclear if PSA testing is actually saving lives.

Click the icon to see an image of a PSA blood test.

Indications for Biopsy. A biopsy is usually performed to confirm or rule out cancer after screening tests that report the following:

• PSA level of 4.0 ng/mL or higher. Some evidence indicates that men with an initial test showing PSA levels above 4.0 should take a second PSA test several weeks afterward before having a biopsy, since many non-malignant factors can increase PSA levels.(Of note: some experts urge biopsies even if PSA levels fall below 4.0 mg, particularly in men under 60, since lower levels do not necessarily rule out cancer.)
• Abnormal digital rectal examination (DRE).

Men with abnormal results from both tests have a 60% chance of prostate cancer. The chances for cancer if only one test is abnormal are considerably lower. To further complicate matters, biopsies themselves may miss very small cancers detected by PSA levels alone.

Factors Affecting PSA Levels. 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. For example, using PSA screening, one study suggested that 15% of Caucasians and 37% of African-Americans are overdiagnosed with prostate cancer based upon PSA results. Some experts believe that there should be different scales for determining risk among these groups, but there is still not enough information to determine 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 older than 65 who have low PSA levels are at such low risk for prostate cancer that they may be able to forgo further testing.
• Benign Prostatic Hyperplasia (BPH) and Its Treatments. Between 25% and 56% of patients with BPH have elevated PSA levels. Certain surgical treatments for this condition can also elevate PSA.
• 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 before testing 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. 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. It is possible that PSA screening could result in the detection of some possible cancers that would never have bothered the patient and would never have posed a threat to his life.

PSA Tests and Effects on Mortality Rates. It is not yet known if PSA tests used for screening actually save lives. Deaths from prostate cancer, for instance, have declined in the U.S. 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. Studies in 2002 and 2003, in fact, have found no relationship between increasing PSA screening and declining mortality rates in prostate cancer. A major important study on this issue is under way.

PSA Test Variations

To improve the accuracy of the PSA tests, particularly when PSA levels have risen to an intermediate range of 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 binding to other proteins 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 if an elevated PSA level could mean cancer:

• A free-to-total PSA ratio of 20% or lower, plus total PSA levels of 4 to 10 ng/mL, are 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 more than 20% plus normal or even moderately elevated total PSA tend to indicate the presence of other, benign conditions, such as benign prostatic hyperplasia (but it still does not rule out cancer).

Some studies have reported that adding a test for free PSA may improve prostate cancer detection by roughly 40% and may also reduce the need for unnecessary biopsies. In addition, any cancers that the test misses would not develop into significant disease for many years, providing ample opportunity to identify them before they became serious. Not all studies support its advantages, however, compared to measuring total PSA alone, and to date there is no consensus among physicians for how it can be used.

Complexed PSA Test. Complexed PSA (cPSA) is a form of circulating PSA that is bound to a molecule called 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, although a major 2002 European study was very favorable.

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.) A major comparison study in 2002 reported more accurate results than with complexed PSA.

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.

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. It should be noted that biopsies can still miss cancers if they are very small.

• 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 cancer is still suspected after negative results, such as in the following circumstances:

• PSA levels are high. Two or more biopsies may be taken if a man has very high PSA levels and still has normal results on a biopsy. Even men with mildly elevated PSA (between 4 and 10 ng/mL) who test negative may be given a repeat biopsy. Cancer will be detected in about 10% of this group. Whether a third biopsy is useful in these men if they still test negative after a second biopsy is uncertain.
• DRE results are abnormal.
• Ultrasound results are abnormal.
• 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 third and fourth biopsies tended to be nonaggressive with favorable outlooks.

Investigative Screening Tests

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.

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 to Determine Severity of 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 are 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.

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.

Serum Acid Phosphatase. High levels of this enzyme indicate a more aggressive disease and the need for intensive treatments.

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 free testosterone could be a marker for aggressive disease. (Free testosterone, as with free PSA, is not chemically bound.)

Genetic Markers. Researchers have identified a genetic marker (EZH2), which may prove to be an important marker for aggressive prostate cancer. It may, in fact, prove to be a better predictor of outcome than the tumor grade, stage, or surgical margins. Other genes beings studied are those that regulate tumor growth (e.g., p53, p27, bcl-2).

Other Markers. Other markers being investigated for predicting cancer progression include prostate-specific membrane antigen, prostatic acid phosphatase, and growth factors.

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. 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.

A radiotracer is injected into a peripheral vein. As the radiotracer decays, gamma radiation is emitted and is detected by a Gamma camera. When the tracer has collected in the target organ the area is scanned. Radionuclide scans can detect abnormalities such as fractures, bone infections, arthritis, rickets, and tumors that have spread, among other diseases.

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. Advanced MRI techniques are showing promise for staging and planning treatments.

Click the icon to see an image of a CT scan.

Click the icon to see an image of a MRI.

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.

Staging and Grading

Physicians are continually searching for methods to determine how aggressive a given prostate cancer is in an individual patient 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 (still within the prostate gland) 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.

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.

M Stages

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

Jewett Staging System

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

The Gleason Grading System

Tumors are assigned scores according to a scale known as the Gleason system, which measure how well or how poorly organized they are under the microscope. The first step is to grade the tumors:

• 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.

Two-thirds of prostate cancers have a mix of tumor grades. To determine a prognosis, two numbers are assigned, representing the dominant grade and then the minor grade. The cancer is then "scored" by adding the dominant grade plus the minor grade. For example, a tumor with a dominant grade of 3 and a minor grade of 4 are given a Gleason 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, with 15-year survival rates of 15% to 40%.

Treatment Options by Staging and Grading

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.

Click the icon to see an illustrated series detailing prostatectomy surgery.

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) following 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 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.

Click the icon to see an illustrated series detailing transurethral resection of the prostate.

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 M0 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. In May 2004, the FDA approved docetaxel (Taxotere) injection in combination with prednisone for treatment of patients with advanced metastatic prostate cancer. Other docetaxel-based chemotherapy regimens are also being investigated.

• 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. Radiation 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.

Treatment for Localized Prostate 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 with lower-risk tumors) involves lifestyle change and careful monitoring for cancer progression. Treatment at that point may be hormonal agents, radiation, or surgery, depending on its extent.

Therapies to suppress androgen (male hormones) may be beneficial as additional treatment in some cases. Unfortunately, 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.

Lack of Data on Survival Rates. To date, neither any treatment nor watchful waiting has emerged with a survival advantage. For example, an important 2002 study reported that radical prostatectomy reduced deaths specifically from prostate cancer compared to watchful waiting but it had no advantage in terms of overall survival rates. The average age of the men was 65. Another 2002 study reported that survival rates were higher after radical prostatectomy than with radiation in men in low to moderate risk categories. However, some experts argued that the radiation used in the studies did not reflect new advances. There was no survival advantage from either approach in higher-risk patients.

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. 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 for higher-risk disease. 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:

• Radiotherapy generally causes more bowel problems than surgery does, 30% to 35% versus 6% to 7%, according to a 2001 study. In a 2003 meta-analysis, the risk for impotence in radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy.
• Prostatectomy causes more urinary incontinence (39% to 49% versus 6% to 7% for radiotherapy patients) than radiotherapy. Risk for impotence, according to 2002 meta-analysis, ranges from 66% after nerve-sparing prostatectomy to 87% after cryotherapy. In spite of these adverse effects, a 2002 study reported no meaningful differences in well-being or quality of life during a four-year period in men who chose surgery versus those who chose watchful waiting.
• Watchful waiting could lead to cancer growth that eventually obstructs the urinary tract (which can happen with the treatments as well).It may also impose an emotional burden on men who live with the possibility of progressive cancer and its difficult treatments. Some 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 for cancer progression. 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 to the point where treatment may be necessary. Patients should exercise and eat healthy foods. 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 is that aggressive therapy is suitable for those who have a life expectancy of more than 10 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 (e.g., 3 to 13 ng/mL) 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. (Of note, a study in 2002 suggested that in men who have prostate cancer, PSA levels between 2 ng/mL and 9 ng/mL are not useful in predicting how aggressive the cancer is or in determining treatment.)

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%) than radiation treatment but has fewer bowel complications. Impotence rates are about the same. 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 candidate, but having decided against an operation.
• The risk for incontinence (less than 10%) is much lower than with surgery, although bowel problems occur in about a third of patients. Impotence rates are about the same.

Choosing Hormonal Treatments

Hormonal treatment in prostate cancer uses drugs or surgery (orchiectomy) to suppress or block male hormones (androgen), particularly testosterone and dihydrotestosterone. Hormone therapy is used for advanced and metastatic cancer and may be used if treatment for localized prostate cancer has failed and cancer recurs (as indicated by rising PSA levels). Side effects can include decreased bone density, decreased muscle mass, hot flashes, and enlargement of breasts.

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. There is some controversy to this approach, however, since androgen deprivation can significantly impair quality of life and survival benefits of the treatment at this stage is uncertain.

Hormonal Treatment Before or After Surgery. Some investigators are finding benefits from using hormone therapy before surgery (neoadjuvant therapy) to reduce the tumor size, although it is not clear yet if this approach has survival benefits. 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 or With Radiation. Hormonal drugs combined radiation therapy may improve survival rates in moderate- or high-risk groups. Patients may need to take these agents long-term (e.g., three years) to improve outcome. Hormonal agents used before radiation (neoadjuvant therapy) may be helpful in shrinking enlarged glands so that brachytherapy (radiation implants) can be used. An important study published in 2004 in the Journal of the American Medical Association found that for men with localized prostate cancer, a 6-month course of hormone therapy combined with radiation treatments produced greater survival rates than radiation treatment alone. Standard medical practice has generally indicated that hormone therapy should be administered for 3 years; this new study suggests that a shorter regimen may be equally beneficial for some patients and may help reduce the side effects that typically accompany androgen-suppressing drugs.

Surgery

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.

Click the icon to see an illustrated series detailing prostatectomy surgery.

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 younger than 70 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.

Click the icon to see an image of catheterization.

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, see Well-Connected Report #50 Incontinence.]

Impotence. Studies suggest that about 40% of men have problems with erection after the procedure. In one study, however, more than 70% said they would have the procedure again. There were few differences in erectile function among all ethnic groups.

Nerve-sparing procedures are proving to be helpful in reducing impotence as well as incontinence. Other techniques may improve sexual function after the procedure. For example, some physicians are investigating methods for sparing the vessels that carry seminal fluid in the prostate. In one preliminary study, when this approach combined with nerve sparing techniques it was more effective at preserving erectile function than the nerve sparing approach alone.

Sildenafil (Viagra) may help restore potency on average in about a third of patients, but some men may do better than others. In one study, for example, 80% of younger men who were potent before surgery and had bilateral nerve sparing procedures responded to the drug. (Only 40% responded with only unilateral procedure.) Viagra is unlikely to be effective for men who had unilateral or no nerve sparing procedures. In those who respond, Viagra may be of benefit for years in the great majority. Viagra may take nine months or longer to become effective. Men who take it, then, might benefit from alprostadil injections started right after surgery to preserve elasticity and help prevent scarring.

Early treatments with alprostadil injections may helpful in restoring erectile function in any case. This treatment maintains blood flow in the penis, and some research suggests that impotence after prostate surgery may be due in part to injury to these blood vessels. In one study, men administered injections every other night for six months. They then started taking sildenafil (Viagra) three months after surgery. At six months, 82% of these men achieved penetration compared to only 52% of men who took Viagra only. The vacuum pump may serve a similar purpose as the injections.

[For more details on this condition, see Well-Connected Report #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 postsurgical 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. 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.

Click the icon to see an image of the pelvic lymph nodes.

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. Impotence rates, however, are much higher. 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).

Radiation Treatments

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. 3-D conformal techniques use computers and a three-dimensional 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. Men who have had transurethral resection of the prostate (TURP) or have a history of lower urinary tract symptoms may be particularly good candidates for 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 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 nausea and loss of appetite. 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 more than 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. In a 2003 meta-analysis, the risk for impotence following radiotherapy varied from 25% with brachytherapy to 45% with external beam radiotherapy. Still, very few studies on brachytherapy have lasted more than two years, so more research is needed.

Sildenafil (Viagra) may help many men experiencing impotence following radiation therapy for local prostate cancer. Early use of both alprostadil injections and Viagra may be even more effective. Other treatments may also be useful. [See Well-Connected Report #15 Impotence.]

Experimental Radiation or Other Nonsurgical Procedures

Investigators are testing radiation treatments that use a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard proton radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions.

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.

Radiofrequency.Radiofrequency is being used to heat and destroy the prostate. Early studies are indicating that this is a promising approach.

Options if Treatments Fail

Indications of Persistent Cancer after Initial Treatment

Rising PSA Levels. If prostate cancer has been eliminated, PSA levels should drop to 0.5 ng/mL 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 2.0 ng/mL, then cancer is most likely still present.
• If PSA levels are between 0.5 and 2.0 ng/mL, 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 for Recurring or Persistent Prostate Cancer After Local Treatment

Treatments for cancer that has recurred after initial therapy is not always clear-cut. If the cancer recurs locally, cure may still be possible:

• Surgery and androgen-suppression therapy may be considered for patients who were first treated with radiation receive.
• For patients who were initially treated with surgery, radiation or androgen-suppression therapy are both options.

If the disease has already spread or if the physician suspects that it may have spread, the patient is typically given androgen-suppression therapy. Chemotherapy agents in combination with hormonal agents are being investigated for patients who fail surgery or radiation.

Androgen-Suppression Therapy. Treatments that block or suppress androgens (male hormones) are often the appropriate response to rising PSA levels after treatment failure. There has been some debate over whether to start this therapy as soon as PSA levels rise or wait until symptoms develop. Some 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. A major analysis in 2002, however, reported that early intervention prolonged survival over a 10-year period.

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: 10 times that of men who have not had radiation. For example, incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures.

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. 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 the cancer is likely to spread. 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%.
• Salvage radiation is radiation therapy more than 6 months after surgery. A 2004 study suggested that salvage radiation could be more beneficial than previously thought, even for men with aggressive prostate cancer. Researchers studied 501 men who had undergone radical prostatectomy (surgical removal of the prostate gland) and subsequently received radiation treatment for recurrent (as indicated by rising PSA levels) cancer. Men with lower Gleason scores and lower PSA levels benefitted the most from salvage radiation. However, even men with higher-grade cancers were able to delay metastatic cancer progression as long as they received radiation at an early stage while their PSA levels were relatively low (less than 2.0 ng/mL).

Other Treatments

Androgen Suppression Guidelines

Male hormones (called 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.

Therapies that suppress male hormones (called androgens) are the mainstay treatment for advanced and metastasized cancer (Stage IV). Such therapies may be in the form of hormonal drugs, orchiectomy (surgical removal of the testicles) surgery, or both. Cure is possible in late-stage prostate cancer, but it is rare. Even without cure, however, treatments can produce striking subjective or objective responses in most patients.

Hormonal therapies are also being investigated in locally advanced prostate cancer following radiation therapy or surgery (called adjuvant therapy) or when used before radiotherapy (neoadjuvant therapy). Studies are suggesting that they improve survival in men at high-risk for progression. The most positive evidence to date is reported with adjuvant hormonal therapy after radiotherapy. Such agents are also being investigated as an alternative to watchful waiting, surgery, and radiation therapy in localized cancer. In a 2003 Japanese study, for example, five-year survival rates in patients using androgen-blocking agents was equal to those in the general population. They have significant side effects and possible long-term complications, however.

Specific Treatments Used to Block Androgen. Androgen-suppression treatments include the following:

• 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. Because orchiectomy is irreversible, about 75% of patients with advanced prostate cancer choose hormonal therapy to block androgens.

Disease Progression and Androgen-Independent Cancer. Unfortunately, in advanced disease, prostate cancer usually returns within about 18 months after antiandrogen treatments. In such cases, the condition is referred to as androgen-independent, and the tumors are not responsive to antiandrogen therapy. The reason for this is still unknown. One theory is that once androgen-sensitive cells have been blocked, cells that are resistant to androgen are stimulated to grow, and the cancer returns. Some studies have detected overexpression of genetic mutations in patients with androgen-independent tumors 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 androgen-independent tumors.

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. A controlled release formulation has been developed that increases the time between injections from 4 weeks to 3 months.
• 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.

LH-RH agonists can also cause PSA levels to rise temporarily. 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 is effective and appears to have fewer severe side effects than other antiandrogens, including loss of sexual interest, osteoporosis, visual disturbance, and interstitial pneumonia. This agent is proving to have survival rates equal to those of maximal androgen blockage (MAb).

An interesting 2002 study suggested that flutamide may actually trigger a pathway that causes cell proliferation, which could be the reason why complete androgen blockage ultimately fails to prevent cancer progression.

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) stimulate the pituitary gland to release luteinizing hormone-releasing hormones (LH-RH). Drugs known as GnRH antagonists, such as abarelix (Plenaxis) and histrelin, block this action. They 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. Certain types of these female hormones may exacerbate heart conditions in high doses, however, 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.

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 may be candidates for 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.

Techniques for Improving Androgen Deprivation Therapies

Maximal Androgen Blockage (MAb). 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 antiandrogens combined with LH-RH agonists or orchiectomy. MAB, however, has considerable adverse effects on quality of life, and studies suggest that survival benefits are very modest compared to androgen suppression with single agents or orchiectomy.

Intermittent Androgen Suppression. Oddly, stopping antiandrogens sometimes causes PSA levels to drop again, a phenomenon called 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, such as finasteride, 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. Some androgen suppressants, such as bicalutamide, may cause less bone loss. The use of estrogens may actually be bone protective. A number of medications are available to help prevent or reduce bone loss. Bisphosphonates are of particular note.
• 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.

Therapies for Androgen-Independent Tumors

Cancer nearly always returns after androgen suppression fails, which is referred to as androgen-independent or hormone-refractory cancer. Researchers are investigating the use of chemotherapy and other agents that affect hormonal triggers of prostate cancer. 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.

Secondary Hormonal Therapies. A number of hormonal agents are being used or tested for relapsed androgen-independent 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 suppression treatments.

Aromatase Blockers. Aminoglutethimide (Cytadren) and similar drugs block aromatase, an enzyme important in estrogen production. 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.

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 p