Prostate cancer

 | March 1, 2008

Prostate cancer

Prostate cancer is slow-growing and may never evolve to the point of being life-threatening. However, some cancers grow and spread and become dangerous. Prostate cancer is responsible for about 9% of cancer-related deaths in men. The hard part is to determine which cancers to treat. Although prostate cancer is the most common cancer among men, it remains difficult to diagnose because it has no dramatic warning signs and progresses so slowly. But its slow growth is also beneficial: unlike cancers that develop rapidly, prostate cancer usually gives you plenty of time to make treatment decisions. There's often no rush.

In the United States, the incidence of prostate cancer rose sharply between 1989 and 1992, fell for a few years, and has leveled off (see Figure 6). The number of deaths from prostate cancer rose slightly at the same time and has now fallen slightly, to about 27,000 deaths per year. More than 70% of cases are diagnosed in men over age 65, and about 90% of men ages 90 or older who die of other causes have evidence of prostate cancer. But while one in six men will be diagnosed with prostate cancer during his lifetime, only one in 35 will die of this disease. Many men who have slow-growing prostate cancer have no symptoms and experience no ill effects for many years.

Many factors, for the individual and the society, explain the shifts in the numbers of men facing prostate cancer. For example, prostate cancer tends to develop in older men, and Americans are living longer than ever before. In addition, technologies for diagnosis have made detection — particularly early detection — more likely. Some experts think the drop in prostate cancer deaths may be due to aggressive screening and treatment; others believe it reflects a generally healthier diet.

Figure 6: U.S. prostate cancer mortality and incidence, 1987–2004 SEER Cancer Statistics Review, 1973–2004.

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Early detection strategies

As with many diseases, prostate cancer is more likely to be treated successfully when it's diagnosed early than if it's found at a later stage. In particular, cure rates are excellent for cancer that is discovered and treated when it's still confined to the prostate gland. Almost 100% of men with localized prostate cancer treated by surgery survive five years or more. But when cancer cells spread beyond the prostate — to lymph nodes, bones, liver, bladder, or rectum — cure rates are extremely low.

Early detection is difficult because most men don't exhibit any symptoms (see "Symptoms of prostate cancer") in the initial stages of the disease. This early lack of symptoms makes regular prostate check-ups particularly important. Screening techniques — the digital rectal examination and the PSA test — offer the best hope for discovering early malignancy. Although these tests aren't perfect, many experts believe they can be lifesavers.

The American Cancer Society recommends that men have DREs annually beginning at age 50 — or at age 45 for African Americans or men with two or more relatives with prostate cancer (see "Are you at high risk for prostate cancer?"). Scientists have identified five genetic markers that may help identify people at high risk.

The benefits of early screening with the PSA test are less clear. You'll need to decide for yourself, with your doctor's guidance, whether to have a PSA test. Much of the debate concerns the accuracy of the test, how the results should be interpreted and used, and the impact of early detection on treatment outcomes. Most men with elevated PSA levels don't have cancer; conversely, many men with prostate cancer have normal PSA readings.

A PSA of 4 ng/ml or below used to be considered normal, but experts are considering whether a lower reading might be a more accurate cutoff point. Studies have demonstrated that a man who has a PSA of 4 to 10 ng/ml has a 20% to 25% chance of having prostate cancer; if his PSA is greater than 10, the likelihood increases to about 60%. But studies have shown that the amount of PSA in the blood does not necessarily correlate with the amount of cancer in the prostate gland, and other studies suggest that the traditional cutoff point of 4 ng/ml may be too high. Some studies have suggested that it be lowered to 2.5 ng/ml. Researchers have found cancers in 10% to 25% of men with "high-normal" PSAs (2.5–4.0). That's almost the same rate of cancer as found in men with PSAs above the normal limit (4.1–10). However, discriminating between a normal and abnormal PSA below 4 ng/ml is very difficult.

Many physicians are now relying on "serial" or "velocity" PSA readings (see "PSA velocity"), which track how much the PSA reading increases from one test to the next. Some studies have shown that the faster the PSA score rises, the higher the risk for cancer.

To complicate matters further, PSA levels appear to depend partly on age — that is, a PSA of 5 might be considered normal for a 73-year-old man, whereas a PSA of 3.9 in someone age 50 might be a red flag. For that reason, some doctors and researchers advocate adjusting "normal" levels for different ages, and some recommend the threshold to biopsy be lowered to 2.5 for men of any age. A combination of PSA testing and DRE may nearly double the detection rate for early-stage prostate cancer. But there's a catch: low-grade, low-volume cancers may progress so slowly that they pose no immediate threat, especially to older men who may die of other causes long before the prostate cancer turns deadly. So, an elevated PSA level may cause needless worry or result in testing and procedures that entail risk for no good reason (see Table 4).

In many cases, a suspicious PSA test will lead to additional procedures (ultrasonography and biopsies) and possibly to major surgery or radiation. Some men with prostate cancer may be treated needlessly. It's extremely important for you to understand the uncertainties and decisions you will face before choosing to have your PSA level measured.

Symptoms of prostate cancer Many men with prostate cancer have no symptoms. But because the prostate gland is enlarged both in cancerous and in nonmalignant conditions such as BPH, these very different conditions share many of the same symptoms. Contact your physician if you notice any of the following signs or symptoms: a need to urinate frequently, particularly at night difficulty starting or stopping urination a weak or interrupted urinary stream an inability to urinate pain or burning when you urinate painful ejaculation blood in your urine frequent pain or stiffness in your lower back, hips, or upper thighs.

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The next step in diagnosis

Doctors will generally suggest additional testing if your PSA level is elevated or the DRE reveals a suspicious area or abnormality. Transrectal ultrasound is often used to pinpoint suspicious areas of the prostate that should be explored further with a biopsy. But even if the ultrasound picture shows a normal prostate, your doctor will usually recommend a biopsy.

If inspection of the biopsied tissue confirms prostate cancer, more tests may be ordered to find out if the cancer has spread to other parts of the body. Computed tomography (CT) or magnetic resonance imaging (MRI) techniques, which use x-rays and magnetic fields, respectively, can produce images that help doctors evaluate the spread of malignant cells to surrounding tissue, including the lymph nodes. A bone scan can reveal areas of bone that contain cancer. But these tests are not always accurate for detecting cancer that has spread beyond the prostate, and not all men need them, particularly if they have tumors with lower Gleason scores and lower PSA levels. In some situations, however, doctors use them to help assign a stage to the cancer.

Table 4: Detecting prostate cancer
First-time prostate screening results for 1,000 men in each age group
Age	Out of 1,000 men, this number had the following results:
	A suspicious DRE, or PSA greater than 4 ng/ml	A biopsy based on suspicious results
50–59	153	107
60–69	280	192
70–79	399	270
Adapted with permission from Urology .

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What stage is it?

Ultimately, the prognosis and decisions about treatment depend on staging. A four-point scale is often used to describe how far the cancer has progressed (see Figure 7). The letters A to D were formerly used to describe these stages, but doctors have turned to a designation using the letters T (for tumor size), N (for lymph node involvement), and M (for degree of metastasis, the spread of cancer to tissues beyond the nearby lymph nodes).

A man's prognosis depends on the stage of the cancer when it's diagnosed. If it's detected when confined to the prostate, it may be cured, in some cases, by aggressive treatment. But stage M+ survival averages only about three to five years.

Figure 7: Stages of prostate cancer Stage T-1 (formerly stage A): Cancers not detected by DRE. These tumors are usually discovered by way of an elevated PSA or analysis of tissues from TURP. T-1A: Involves less than 5% of prostate and a Gleason score of 7 or below. T-1B: Involves more than 5% of prostate and/or a Gleason score of above 7. T-1C (not shown): Detected as a result of an elevated PSA. Stage T-2 (formerly stage B): Palpable cancers confined to the prostate. T-2A: Tumor less than 2 cm, in a single lobe. T-2B: Tumor greater than 2 cm, or in more than one lobe. Stage T-3 (formerly stage C): Cancers that have broken through the prostate's fibrous capsule to nearby tissue. Growth through prostate capsule. Stage N+ or M+ (formerly stage D): Cancers that have metastasized to the pelvic lymph nodes or to distant parts of the body, such as the bones. N+ (D1): Spread to lymph nodes. M+ (D2): Spread beyond pelvis or to bone or lung.

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How fast is it growing?

Doctors also use another assessment scale to predict the behavior of the prostate cancer, based on a microscopic evaluation of the biopsied tissue cells. A numerical grade, called the Gleason score, describes the cancer based on its aggressiveness — that is, how rapidly its malignant cells are multiplying.

In about half of all cases, there is more than one type of cancerous cell in the prostate. Pathologists evaluate the most common type of cancer cell and attach a number to it. If these cells deviate only slightly from normal prostate tissue, they are likely to be slow-growing. In this case, the grade is 1. On the other hand, if they have changed to look more like cancer cells and are therefore likely to spread quickly, the grade is 5, the highest rating.

The same grading process is repeated for the second most common type of cell. Combining the two scores yields a Gleason score of 2 to 10. The higher the number, the faster the malignant cells are multiplying. Today, in practice, doctors almost never see a Gleason score of 2, 3, or 4; rather, the score usually ranges from 5 to 10. So, a Gleason score of 5 or 6 indicates a tumor that is on the slower-growing end of the scale.

Physicians use both the grade and the stage in evaluating the probable course of the illness, the likelihood of cure, and the best possible approaches to treatment.

Are you at high risk for prostate cancer? You may have a higher-than-average risk for prostate cancer if you answer "yes" to any of these questions: Are you 55 years old or older? Prostate cancer is a disease of older men, and the risk increases with age. The average onset is at age 70, and about 98% of cases occur in men over age 55. As life expectancy continues to rise, the incidence of prostate cancer will probably increase with it. Do you have a family history of prostate cancer? A man who has a father, brother, or son with prostate cancer has two to three times the risk of developing the disease as a man whose first-degree male relatives don't have the disease. A man who has two or more first-degree relatives with prostate cancer faces a risk five to 10 times greater than one who has no family history of the disease. Are you African American? African American men have the highest rate of prostate cancer in the world. Although the reasons are unclear, researchers suspect a number of variables may be involved. For example, testosterone stimulates the growth of this cancer, and on average, African American men tend to have higher levels of this hormone than whites. Also, the prostate cancer death rate may be higher in this population because African Americans are often diagnosed at a later stage, when the cure rate is much lower. Is your diet low in fruits and vegetables? Men who live in affluent Western countries have a higher risk for prostate cancer, and researchers believe this is linked to diet. To date, the food that has been linked most closely to an increased risk for prostate cancer is calcium. In the meantime, experts generally recommend a diet high in fruits and vegetables and lower in dairy and calcium.

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Treating prostate cancer

Choosing a treatment for prostate cancer can be a complicated matter. Often there is no obvious choice and you will need to weigh your options carefully and make a decision, with the help of your doctor, based on many factors — not only the stage of your cancer, but also your age, lifestyle, and risk of side effects such as urinary incontinence and erectile dysfunction.

The good news is that the odds of surviving prostate cancer are better than ever. In the mid-1970s, according to the American Cancer Society, about two-thirds of men with the disease lived at least five years, but in the 1990s, that figure had increased to more than 93%. And now more than half of all men diagnosed with prostate cancer survive at least 15 years. This impressive change is partly due to increased diagnosis based on widespread PSA screening, but it also reflects improved treatment.

Although as many as one in six men will be diagnosed with prostate cancer during his lifetime, researchers believe that most prostate malignancies will never become life-threatening because of their slow-growing nature and because this cancer develops late in life. Many men — perhaps a third of those over age 50 — have early, undiagnosed prostate cancer; but again, most of these malignancies will never pose a significant risk to their well-being. In one study, men ages 65 to 75 who were diagnosed with early-stage prostate cancer lived about another 16 years — about the same as men who didn't have prostate cancer.

There are several options for treating prostate cancer: active surveillance; surgically removing the prostate gland; radiation, including external beam or implanted pellets; cryotherapy; ablative hormone therapy; and chemotherapy. These treatments may be used alone or in combination, depending on a man's age, the stage of the cancer, and personal preferences regarding the side effects of the treatments and the lifestyle changes they may entail. These treatments are continuously being improved and refined in ways that increase their effectiveness and reduce the unwanted side effects, such as urinary incontinence and erectile dysfunction.

But the wide variety of treatments can be confusing for patients and doctors alike. In fact, the American Urological Association's Prostate Cancer Clinical Guidelines Panel concluded that, at present, we can't prove that one treatment is better than another. For example, the panel recommends that men with early prostate cancer be given a choice of active surveillance, radiation, or surgery. With this in mind, the following sections describe the available treatments to assist you in making a decision based on your doctor's recommendations and how a particular treatment will likely affect your quality of life. As you evaluate your treatment options, think not only about your situation today, but also about where you expect to be in five or 10 years — because chances are, you'll still be alive (see Table 5). For example, if you look forward to spending as many years as possible with your spouse and grandchildren, you might choose the treatment that gives you the best chance of survival, with less regard for possible side effects. On the other hand, if you are a sexually active single man, you may want to focus on treatment options that give you the best chance to preserve sexual function.

Table 5: How long will you live?
Life expectancy for men The older you get, the longer you are likely to live. Life expectancy is one factor in treatment decisions.
Current age	Life expectancy
0 (birth)	74.7
10	75.5
20	75.8
30	76.5
40	77.2
50	78.5
60	80.4
70	83.4
80	87.9
90	94.3
100	102.2
Source: National Vital Statistics Report, 2007

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Active surveillance (watchful waiting)

Some men diagnosed with prostate cancer need no treatment; for example, men with slowly progressing stage T-1 cancers shown to be low-volume during biopsy, or with Gleason scores of 5 or 6, particularly if they have other illnesses or a life expectancy of less than 10 more years. Also, many older men, especially beyond age 75, are more likely to die of another condition before their prostate cancer becomes troublesome or dangerous, and they may face greater risks from the rigors of surgery or other treatments than from the cancer itself. For these groups, active surveillance (also called observation or "watchful waiting") may be the most sensible option. This tack involves close monitoring, but no treatment, of a newly diagnosed cancer.

Active surveillance is not a stopgap measure. Rather, it is an active decision not to pursue treatment, based on careful consideration of life expectancy, the risk of cancer progression, and the potential side effects of treatment. If you are likely to spend the months in between PSA tests or DREs worrying that your cancer is growing, then this may not be the right choice for you.

Active surveillance has created a cauldron of controversy within medical circles, with critics pointing to the sometimes narrow window of opportunity during which prostate cancer can be cured. Once the cancer progresses beyond the prostate, it becomes extremely difficult to treat, so for some men, they warn, watchful waiting can be a death sentence. On the other hand, some prostate cancers may take 15 to 20 years or more to grow and cause little harm. Overtreatment becomes a greater risk to the well-being of men with slow-growing tumors.

Virtually all doctors agree that younger men — say, those ages 55 to 60, with an aggressive cancer in the early stages — require treatment. But many men are in a gray zone, where age, cancer grade and stage, PSA level, other illnesses, and the potential adverse effects of cancer treatments must be weighed together. After all, no treatment is risk-free, and whether a patient chooses surgery or radiation, serious side effects can diminish his quality of life.

When is it safe to wait? There are a lot of factors to weigh and no definitive answer to this question. The Department of Veterans Affairs is conducting a large, long-term study comparing men treated conservatively or with surgery. This study may shed new light on the best candidates for active surveillance. Until more information is available, one option is to postpone treatment but continue to have regular DREs (to monitor tumor growth) and periodic PSA tests (to check for increases in blood levels that might indicate a progression of the cancer). These follow-up tests should be scheduled every four to 12 months, depending on a man's age, biopsy results, and anxiety level.

If PSA readings increase sharply or if the doctor feels a new lump during a DRE, the cancer may be advancing, and treatment can be reconsidered. A change in urinary habits can also signal that it's time to begin active therapy. And any man who tends to worry a great deal might prefer active treatment over waiting and worrying, even if his tumor is slow-growing.

Prostate cancer specialists If you are diagnosed with prostate cancer, you are likely to encounter one or more of the following medical specialists: Urologist: A urologist treats disorders of the urinary tract and male reproductive system, including prostate cancer, BPH, and prostatitis. Urologic oncologist: Urologic oncologists are surgeons who specialize in treating cancer of the urinary tract and male reproductive organs. Radiation oncologist: Radiation oncologists specialize in the use of radiation therapy to treat cancer. If you choose radiation therapy, a radiation oncologist will develop your radiation treatment plan, monitor you while you are receiving therapy, and treat any side effects from the radiation. Medical oncologist: Medical oncologists treat cancer with medical therapies. For prostate cancer, these would include hormone therapy and chemotherapy. These specialists would also handle general medical problems that might arise over the course of the disease. Other medical specialists that may participate in your care include oncology nurses, dietitians, physical therapists, occupational therapists, social workers, and psychologists or counselors.

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Surgery

Men have better options today than they used to. Radical prostatectomy, the gold standard for the surgical treatment of prostate cancer, is now safer and has fewer side effects than ever before. A 2003 landmark study by Scandinavian researchers provided the first clear evidence that surgical removal of the prostate gland improves survival for men who were diagnosed by DRE. Results showed that after six years, 4.6% of men who had prostatectomy died from the disease, compared with 9% of those who relied on active surveillance. (Results of a similar study under way in the United States, known as PIVOT, will help determine the best treatment choices for men diagnosed with the PSA test.)

The best candidates for this surgery are men whose disease is confined to the gland itself (stages T-1 and T-2), who are under age 70, and who are in good general health. This procedure is technically difficult, so choose a surgeon who is highly experienced in this operation to obtain the best outcome and fewest side effects. The best results, in terms of avoiding complications such as urinary incontinence, are obtained by surgeons who do large numbers of these procedures in high-volume hospitals, according to evidence published in The New England Journal of Medicine in 2002.

Prostatectomy is a very safe operation. The chances of death during or directly after a radical prostatectomy are less than 1%. Still, this is a risk worth taking into consideration.

Undergoing radical prostatectomy. This surgical procedure usually requires that the patient be under general anesthesia. The goal of surgery is to remove the patient's prostate and the seminal vesicles (saclike glands that release fluid which becomes part of semen). In some cases, the surgeon also removes pelvic lymph nodes.

To perform a radical prostatectomy, the surgeon may use any of several techniques. In one method, known as the open retropubic technique, the surgeon removes the prostate and lymph nodes through an incision in the abdomen. In a newer, laparoscopic method, the surgeon removes the lymph nodes and prostate through several keyhole incisions in the abdomen. A variation of the laparoscopic method that is becoming more common is robot-assisted prostatectomy. With this technique, the surgeon sits at a console while directing the instruments placed through several keyhole incisions. Another option is the perineal technique, in which the surgeon works through an incision in the area between the scrotum and the anus (the perineum).

The method used generally reflects your surgeon's preference. In the United States, most surgeons used to practice the open retropubic technique, which has a low rate of complications. However, many now use the robot-assisted laparoscopic technique, which is technically less difficult to perform than the standard laparoscopic technique. Early comparison studies of robotic and standard laparoscopic techniques show no differences in outcomes when each is performed by an accomplished surgeon. Some surgeons suggest that laparoscopic surgery can shorten recovery time. Although the complication rate may differ between the open retropubic technique and laparoscopic technique, outcomes appear to be similar. A few surgeons practice the perineal technique, arguing that it causes less pain. The disadvantage to this approach is that it doesn't permit access to the lymph nodes in the pelvis that drain the prostate.

Before taking out the prostate — except in the case of the perineal technique — the surgeon may remove lymph nodes that he or she suspects may have been infiltrated by the cancer. A pathologist will immediately examine the nodes. If cancer is present, the operation will go no further because this means the cancer has spread beyond the prostate, in which case other treatments are more effective than removing the prostate.

If the lymph nodes show no cancer, the surgeon carefully separates the prostate and the seminal vesicles from the surrounding tissues and removes them. Later, the pathologist examines these organs. If the cancer is confined to the prostate, odds are good that the cancer won't return. If the cancer has already spread beyond the capsule surrounding the gland, additional treatment may be necessary.

Recovery usually involves two to three days in the hospital and several weeks at home. The patient will need to urinate through a catheter for a week or two while the urethra heals.

Reducing side effects of surgery. Men have traditionally shuddered at the risks of radical prostatectomy, especially permanent impotence, which used to occur in nearly all cases. But that began to change in the early 1980s, when urologist Patrick Walsh at Johns Hopkins Hospital crafted what he called an "anatomical approach" to the surgery. The operation is performed in a way that attempts to spare the bundle of nerves controlling erections (see Figure 8) and may also reduce the likelihood of other serious side effects, such as urinary incontinence and significant blood loss.

Not surprisingly, almost everyone undergoing prostatectomy wants the nerve-sparing procedure, and it's now available across the country. However, success is not guaranteed. If the tumor is too close to the nerve bundle, the nerves can't be saved. Even if the procedure is successful, it can take six months or more for the tiny nerve fibers — which often stop transmitting impulses when they've been traumatized by the surgery — to heal sufficiently to restore sexual function. Estimates of the number of men undergoing radical prostatectomy who actually regain their ability to have erections range widely, from 25% to 80%.

It's important to choose an experienced surgeon. The likelihood of a successful outcome — in terms of preserving potency, preventing incontinence, and, most important, curing the cancer — generally correlates with experience. The number of procedures a surgeon performs does not necessarily make him better than one who does fewer; however, a minimum of 15 to 20 prostatectomies per year is necessary to be most skilled at the operation.

Recovery of sexual function also depends on age (with best results in men under age 65) and the location of the tumor. Medication may be prescribed to help this process (see "Treating erectile dysfunction and incontinence").

Figure 8: The prostate and its nerves The goal of radical prostatectomy is to cure early prostate cancer that is confined to the prostate by removing the entire gland. Because the prostate is wedged tightly between the bladder and the rectum, it's a delicate task that should be performed by skilled urologic surgeons. Because the nerves that are responsible for erections (shown in black in the illustration above) are often damaged during the operation, impotence is a common complication. Another approach, the nerve-sparing prostatectomy, attempts to preserve potency by removing the prostate without disrupting the nerves.

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Radiation therapy

This treatment uses radiation to destroy cancerous cells. Since many people prefer to avoid surgery if possible, radiation therapy can be a reasonable alternative. There are two ways to deliver radiation: by aiming an external beam of radiation at the tumor, or by surgically implanting small radioactive pellets in the prostate gland. Variations on these techniques, such as three-dimensional conformal radiotherapy and intensity-modulated radiotherapy allow physicians to more accurately target the cancerous area and minimize the exposure of healthy tissue to damage from radiation. To improve survival, radiation therapy is sometimes used in combination with a form of hormone therapy (see "Ablative hormone therapy") known as adjuvant androgen therapy.

There is some controversy over whether radiation is as effective as surgery in treating early prostate cancer, although there's no conclusive evidence in favor of either approach. However, because a small number of cancerous cells can survive after a full course of radiation, there is some concern that the cancer may recur five years or more later. This is a major reason many urologists recommend surgery for men with early cancer who are age 60 or younger, although radiation oncologists often disagree.

Radiation is sometimes used after surgery if tissue that has been removed reveals the cancer has spread beyond the prostate capsule (stage T-3). Or it may be used some months after surgery if a PSA test indicates the presence of residual cancer.

External beam radiation. Most patients receive external beam therapy, in which rays of high-energy radiation are aimed directly at the prostate tumor (and sometimes at nearby lymph nodes). Radiation may be given in the form of photons (conventional radiation) or in the form of protons. The radiation dose is the same, whether delivered as photons or protons. Proton beam therapy is available in only a few centers because it requires a cyclotron (a type of particle accelerator that is prohibitively expensive for many hospitals) to deliver the radiation. At this time, no convincing studies exist to suggest that one form of radiation is superior to the other in the treatment of prostate cancer.

The first step in external beam radiation is a CT scan, which relays an image to a computer that constructs a detailed three-dimensional map of the prostate and seminal vesicles. The map allows the radiation therapist to precisely target the cancerous tissues while shielding the healthy tissues nearby, including the bladder and rectum.

The therapist first places the patient on the table in exactly the right position, then puts lead shielding in place to protect normal tissues, and finally activates the overhead device that delivers the beam of radiation. The treatment is quick and painless, but because the dose must be spread out over time, the treatments are repeated five times a week for eight weeks or more. This time commitment can be difficult if you don't live or work near the hospital.

Brachytherapy. In this procedure, radiation is delivered by "seeds" or pellets of radioactive material that are implanted into the prostate itself. Because it is more convenient for the patient, and recovery time is short, brachytherapy is among the most widely used treatments for cancer that has not spread beyond the prostate. Modern imaging techniques have improved the efficacy of this technique, which was developed in 1922 and revived in the 1970s. Brachytherapy is generally recommended for slower-growing lower-grade tumors.

After the patient receives spinal anesthesia, the doctor places an ultrasound probe in the patient's rectum and a catheter in the bladder. Viewing a computerized map of the prostate, the doctor guides the placement of the pellets, using a needle to insert them through the perineum. This is usually an outpatient procedure, and most men return home as soon as the anesthesia wears off. The patient will need to abstain from sex for about two weeks and then use a condom for several weeks to protect his partner from radiation exposure, but there are usually no other restrictions. Because the pellets stop emitting radiation after a few weeks, they can be left in place permanently.

Some men choose pellet implants because they are more convenient than external beam radiation, requiring only a single treatment. Data suggest that brachytherapy and external beam radiation are equally likely to lead to impotence or incontinence.

When comparing radiation to surgery, brachytherapy rates about the same as prostatectomy in terms of resulting quality of life. For example, a Harvard study published in 2001 in The Journal of Urology found little difference in quality of life between men who had brachytherapy and those who received radical prostatectomies for localized prostate cancer. Over five years, the men who received the radiation pellets enjoyed better sexual function and fewer urinary symptoms than the ones who had radical prostatectomy, although they had worse bowel function. Another study, which also appeared in The Journal of Urology, reported similar findings. However, men who underwent nerve-sparing prostatectomy enjoyed the highest sexual function.

In terms of effectiveness, preliminary data suggest brachytherapy is about as effective as external beam radiation or surgery for low-grade cancers, but less effective for higher-grade tumors. A study of 126 men with localized prostate cancer found that brachytherapy was as effective as radical prostatectomy and external beam radiation in keeping men disease-free for at least five years. However, for men with tumors at an intermediate or high-risk stage, a 1998 Harvard study of 1,872 men published in The Journal of the American Medical Association indicated that radical prostatectomy or external beam radiation therapy are probably better choices. The study found that pellet implants are much less effective than had been thought, and it questioned their use in men with intermediate or late-stage tumors.

Vasectomies: Are they hazardous? A vasectomy is a surgical procedure in which the tubes that carry sperm are cut and sealed. As popular as vasectomies have become among American men (15% of men over age 40 have had this contraceptive surgery), studies periodically associate the procedure with an increased risk of developing prostate cancer. Two 1993 investigations — both conducted by Harvard researchers — suggested that having a vasectomy could raise a man's risk of developing prostate cancer at a later date. But scientists have not found any evidence to support a biological link between the operation and subsequent malignancy. One possible explanation is that men undergoing vasectomies are more health-conscious, visit their doctors more often, and are more likely to have early prostate cancer detected. For now, there's no compelling evidence that vasectomies trigger or stimulate prostate cancer.

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Cryotherapy

This freezing technique is used less often today because its results have not been impressive. For cryotherapy, a doctor uses liquid nitrogen to freeze cancerous prostate cells. Using transrectal ultrasonography as a guide (see "Ultrasound"), the doctor inserts up to five metal probes into the prostate through the perineum to deliver the liquid nitrogen to the prostate gland. Meanwhile, a catheter containing a warming solution is inserted into the penis to protect the urethra and surrounding tissues. Once the prostate is frozen, the liquid nitrogen is turned off and the gland is allowed to thaw. The best results are achieved when the process is repeated.

Many urologists don't endorse cryotherapy because its efficacy over the long run has never been proved in trials that compare it with radiation therapy or radical prostatectomy. Preliminary data suggest that about 15% of men who receive cryotherapy as the primary treatment for prostate cancer relapse within two years, and about 45% have recurrences within five years. Unlike radiation or surgery, however, cryotherapy can be repeated to treat recurrent cancer, and it can be used for men who relapse after radiation.

Like other treatments, cryotherapy has side effects. Impotence is very common, and urinary incontinence is both more frequent than with radiation and increasingly likely with additional treatments. Rectal complications can also be a significant problem.

Table 6: Ablative hormone therapy medications
Drug name	Side effects	Comments
LHRH agonists
goserelin (Zoladex) histrelin (Vantas) leuprolide (Lupron Depot) triptorelin (Trelstar)	Hot flashes, impotence, decreased libido, fatigue, weight gain, anemia, osteoporosis.	Injected or implanted.
GnRH antagonist
abarelix (Plenaxis)	Hot flashes, sleep disturbances, small chance of a serious allergic reaction.	Not available to new patients in the U.S.
Anti-androgens
bicalutamide (Casodex) flutamide (Eulexin) nilutamide (Nilandron)	Hot flashes, impotence, decreased libido, breast tenderness and swelling, nausea, and diarrhea. Rarely, liver failure.	Taken orally. Liver function should be checked periodically.
Estrogens
diethylstilbestrol (DES, Stilphostrol)	Hot flashes, nausea, breast swelling and tenderness, blood clots.	Taken orally. Not commercially available in United States, except in compounding pharmacies.

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Ablative hormone therapy

For men whose cancer has spread beyond the prostate and into the lymph nodes or bones, the prognosis is less hopeful. Patients with stage N+ or M+ disease are usually offered ablative hormone therapy (see Table 6). The term ablative refers to the fact that a hormone — in this case testosterone — is being suppressed, rather than replaced or supplemented (see Figure 9). Androgens, the family of sex hormones that includes testosterone, can fuel tumor growth and progression; suppressing these hormones can help relieve symptoms and perhaps slow the course of the disease. For men with early-stage disease, physicians may also suggest ablative hormone therapy to help shrink the prostate before radiation, a technique called neoadjuvant therapy. When given after surgery or radiation to prevent recurrence, it is called adjuvant therapy. Standard ablative hormone therapy, which is also sometimes referred to as androgen deprivation therapy, formerly meant the surgical removal of both testicles. This procedure, known as orchiectomy, reduces the circulating level of testosterone, the male hormone that stimulates the growth of prostate cancer cells. But because many men find the idea of having their testicles removed difficult to accept, doctors often recommend injectable drugs — primarily luteinizing hormone–releasing hormone (LHRH) agonists — that dramatically lower testosterone levels and slow the cancer. Anti-androgens, another class of drugs, are also occasionally used.

Figure 9: How hormone therapy affects the androgen cascade Androgens are male sex hormones that fuel the growth of prostate cells, including prostate cancer cells. Hormone therapy — also known as androgen-deprivation therapy — seeks to cut off the fuel supply. But different therapies work in different ways. The androgen cascade A. The hypothalamus releases pulses of luteinizing hormone–relaxing hormone (LHRH), which signals the pituitary gland to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). B. LH travels through the bloodstream. When it reaches the testicles, it binds to specialized cells that secrete testosterone into the bloodstream. C. In the prostate, the enzyme 5-alpha-reductase converts testosterone and other types of androgens into dihydrotestosterone (DHT), which stimulates the growth of prostate cells — and fuels the growth of cancer, if it is present. Centrally acting therapies LHRH agonists flood the pituitary gland with messages to crank out LH. This causes a temporary surge of testosterone until receptors in the pituitary are overloaded. Then testosterone levels drop sharply. The GnRH antagonist acts against gonadotropin-releasing hormone, jamming receptors in the pituitary gland so that it cannot respond to pulses of LHRH sent by the hypothalamus. This prevents the LH signal from being sent — and no testosterone is made in the testicles. The hormone diethylstilbestrol (DES) inhibits secretion of LHRH from the hypothalamus. Peripherally acting therapies Orchiectomy removes the testicles, preventing testosterone production. Anti-androgens block the interaction of DHT with the androgen receptor located in the prostate cancer cell. Stimulation of this receptor allows cells to grow. By blocking this stimulation, anti-androgens prevent prostate cancer cell growth.

The injected LHRH agonists inhibit the production of luteinizing hormone in the pituitary gland. Because luteinizing hormone stimulates testosterone secretion in the testicles (where 90% to 95% of androgens are produced), inhibiting it lowers testosterone levels. LHRH agonists are injected into muscle or fat tissue under the skin. The first LHRH agonists were self-injected on a daily basis by patients. Today, "depot" formulations are available, which can be implanted under the skin to provide extended release of the medication for anywhere from a month to a year.

LHRH agonists can cause a temporary surge in testosterone that generally lasts from three weeks to one month. Anti-androgens may be prescribed in conjunction with LHRH agonists to counteract that surge, a strategy known as combined hormone blockade. Anti-androgens, taken orally, block the effect of testosterone on the prostate by blocking the attachment of testosterone to its receptors on the cells.

Abarelix (Plenaxis), a gonadotropin-releasing hormone antagonist, also blocks the release of luteinizing hormone, but it does so without triggering a testosterone surge. However, for commercial reasons, the manufacturer is not currently making abarelix available to new patients.

Ablative hormone treatments produce the same benefits as orchiectomy, but they require patients to take the prescribed medications as scheduled. These drugs may also cause some side effects. Because the drugs interfere with testosterone, sexual function is often a casualty of ablative hormone treatment. Many men experience impotence and a loss of sexual desire. When treatment is stopped, however, sexual function usually returns. Hot flashes, nausea, and diarrhea are also common. In addition, the anti-androgens have been linked with liver failure and should be used with caution. Patients who take them should have routine tests of liver function. Also, reduction in bone density and muscle mass occurs in some patients, and breast enlargement can be a significant problem.

Sometimes the physician prescribes an LHRH agonist and an anti-androgen in combination — the former to lower hormone levels, and the latter to block the receptors in the prostate from any residual male hormones. So far, studies have not shown any one form of hormone therapy to be superior. All appear to work equally well, according to a report by the federal Agency for Health Care Policy and Research. For example, the report concludes that "combined hormone blockade" is no more effective than other hormone strategies.

Evidence supports the use of radiation and ablative hormone therapy in combination. A 2004 study in The Journal of the American Medical Association supported the use of such combined therapy for patients with early-stage prostate cancer. In this study, 206 men with early-stage prostate cancer received either radiation alone or radiation plus six months of hormone therapy. After five years, the men who received radiation plus hormone therapy had significantly higher survival and significantly lower relapse than men who received radiation only. Additional studies on the long-term benefits of combined treatments are under way.

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Chemotherapy

Chemotherapy is rarely used to treat early prostate cancer, because it is most effective for fast-growing malignancies that spread quickly — qualities that usually don't apply to prostate cancer. However, it's routinely used by men with advanced cancer who no longer respond to ablative hormone therapy, a situation referred to as hormone-refractory prostate cancer.

Cancer cells usually grow more rapidly than normal cells. Chemotherapy works against them by interfering with their growth and reproduction. However, the drugs are absorbed by tissues throughout the body, so healthy cells can also be harmed, especially those that divide quickly. The damage that chemotherapy does to normal cells can cause side effects. For example, hair loss, one of the classic side effects of chemotherapy, occurs because the drugs damage the cells of hair follicles. Cells in the bone marrow, mouth, stomach, and intestines are also commonly affected.

Aside from hair loss, the treatment may cause fatigue, mouth sores, nausea, and infertility. The presence or absence of side effects, however, doesn't indicate how well the therapy is working. Most men find the side effects manageable, and the effects don't last very long. In a few months, the chemotherapy is finished, their bodies recover, and they steadily return to feeling normal.

The drugs are given in pill form or intravenously. They are usually taken in cycles, with each period of treatment followed by a rest period. This cycle can be daily, weekly, or every three to four weeks, depending on the drug and your tolerance. Combinations of chemotherapy drugs are often more effective than single drugs, but even these combinations aren't particularly effective for advanced hormone-refractory prostate cancer (see Table 7).

Table 7: Chemotherapy for advanced prostate cancer
Drug name	Side effects	Comments
docetaxel (Taxotere)	Hair loss, nausea and vomiting, drop in blood cell count.	These anticancer drugs may be used in specific combinations, such as estramustine plus docetaxel. They are used when cancers become hormone-refractory, that is, when they cease responding to hormonal treatment.
estramustine (Emcyt)	Nausea and vomiting, fatigue, headache, drop in blood cell count, blood clots.
mitoxantrone (Novantrone)	Nausea and vomiting, hair loss, fatigue, drop in blood cell count.
paclitaxel (Taxol)	Hair loss, fatigue, drop in blood cell count, numbness and tingling in hands and feet (usually after long-term use).

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What are the risks for impotence and incontinence?

Most treatments for prostate cancer, aside from chemotherapy, pose a risk for impotence and incontinence. The best way to reduce the severity of these side effects is to choose an experienced surgeon or radiation oncologist. Not all treatments have been fully studied for their effects on sexual and bladder function, but good information is emerging for at least some of these treatments, particularly radical prostatectomy and external beam radiation.

Sexual function. Men who undergo prostate surgery may find their erectile function impaired immediately after surgery, but some men gradually regain some functioning as damaged nerves heal. Those who have radiation therapy often lose erectile function gradually, usually over one to two years. A study of 1,156 men in the Journal of the National Cancer Institute in 2000 reported that two years after surgery, 80% of men who underwent radical prostatectomy could not maintain an erection sufficient to have intercourse. A follow-up study published in 2004 reported that five years after surgery, erectile dysfunction was more common in men who underwent surgery (79%) compared with those who had external beam radiation (63%). However, overall sexual function was about the same in both groups, possibly because of the gradual decline in sexual function in men who underwent external beam radiation.

Incontinence. Urinary incontinence is less common. The Journal of the National Cancer Institute study in 2000 found that two years after radical prostatectomy, 28% of the men were using pads to absorb leakage. Men who undergo external beam radiation fare better. In one large study, only 3.5% of men reported leakage two years after external beam radiation. And the 2004 study comparing radical prostatectomy to external beam radiation found that after five years, 14% to 16% of men who had radical prostatectomy were incontinent, compared with only 4% of men who had external beam radiation. Bowel urgency and painful hemorrhoids were more common in men who had external beam radiation.

Sex and prostate cancer The prostate's job is to contribute fluid to semen. Since the gland is so intimately involved in sex, men often wonder if sexual activity has an impact on prostate cancer, either increasing risk or providing protection. Results published in 2004 from the Health Professionals Follow-up Study suggested that a high frequency of ejaculation is linked with a lower risk for prostate cancer. Over a period of eight years, researchers collected data from 29,000 men, ages 46 to 81, and divided them into five categories based on frequency of ejaculation: the lowest category was zero to three ejaculations per month, and the highest was 21 per month or more. Most categories had no effect on prostate cancer risk, but the group with the most frequent ejaculations showed an 11% decrease in risk for prostate cancer. Another group of researchers evaluated the sexual histories of 1,456 men, ages 40 to 64, in King County, Wash. About half (753) of these men had prostate cancer. Results showed that sexually transmitted disease was linked with prostate cancer, but the link was very weak. In addition, having a greater number of female sexual partners was linked to a higher risk for prostate cancer. Men who had sex with 30 or more partners during their lives were 2.3 times more likely to develop prostate cancer than men with only one partner. Even a more modest exposure of two to four partners was linked with nearly double the risk.

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Preventing prostate cancer

The cause of prostate cancer is unknown, which means it's hard to suggest preventive strategies. Researchers have not found a powerful association with lifestyle, although there is some evidence that diet may play a role. The science of food and cancer prevention is a moving target that, so far, hasn't produced clear-cut advice for prostate cancer prevention. Still, some interesting trends are emerging. A Western diet seems to somehow raise the risk for prostate cancer, but the details of exactly which components of the Western diet may be responsible are only beginning to become clear.

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Calcium

A number of studies have linked an increased risk for prostate cancer with high calcium consumption. One of these is the Health Professionals Follow-up Study, which showed that men who consumed more than 2,000 mg of calcium a day had more than four times the risk of developing prostate cancer compared with those who consumed only 500 mg a day. (One cup of low-fat yogurt contains about 380 mg of calcium; one cup of skim milk has 300 mg.) A Swedish study also confirmed a higher rate of prostate cancer for men who consumed more calcium. Researchers have separated calcium from the other components of dairy products, such as dairy fat. The nutrition cohort of the Cancer Prevention Study II also showed that calcium, whether or not it came from dairy products, raised the risk for prostate cancer.

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Red meat

Previously, research seemed to point to a connection between red meat and prostate cancer, but more recent data do not bear this out. The National Health and Nutrition Examination Survey (NHANES) followed 3,779 men for 10 years and found no connection between prostate cancer and a diet high in meat and carbohydrates. Neither total fat nor saturated fat showed any connection to an increased risk for the disease.

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Fruits, vegetables, and their nutrients

Thus far, selenium, found in certain plant foods, is showing the most promise for prostate cancer prevention. The amount of selenium in the soil, which varies by region, determines the amount found in the plant. But your selenium intake isn't wholly dependent on the fruit and vegetables you eat; animals that eat plants grown in selenium-rich regions also have higher levels. In the United States, the highest soil concentrations are found in the high plains of northern Nebraska and the Dakotas.

A study of 1,312 men at the Arizona Cancer Center showed that those who took 200 micrograms (mcg) of selenium per day were 63% less likely to get cancer of any kind and, in particular, reduced their risk for lung, colorectal, and prostate cancers. And a 2005 analysis of 16 individual trials linked a moderate consumption of selenium to a 26% reduction in the risk of developing prostate cancer. Other large trials are under way, including the Selenium and Vitamin E Cancer Trial (SELECT), which involves some 32,000 participants.

The evidence that a diet rich in fruits and vegetables may reduce the risk for prostate cancer is becoming more tenuous. In 1995, a large epidemiological study by Harvard researchers found that men who ate at least 10 servings a week of tomato-based foods reduced their risk for the disease by 45%, while those who had four to seven servings lowered their risk by 20%. Researchers suspected the protective agent was lycopene, a carotenoid and antioxidant found mostly in tomatoes and tomato products. However, a 2007 review by the FDA published in The Journal of the National Cancer Institute found no evidence to support an association between lycopene and a reduced risk of prostate cancer. What's more, the study found only "very limited" evidence of a link between tomato consumption and reduced risk of prostate cancer.

Another blow to lycopene came with a 2007 American Journal of Clinical Nutrition study, which found no association between the consumption of carotenoids (such as lycopene) and prostate cancer prevention. The same study also looked at retinol and tocopherols (vitamin E); the researchers found no link between intake of these nutrients and a reduced risk of prostate cancer.

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What about vitamins?

A study published in 2007 found that not only did vitamins — in this case, multivitamins — not help, but they may cause harm. The report, published in The Journal of the National Cancer Institute, found that compared with men who did not take multivitamins, men who took them more than seven times a week were 32% more likely to develop advanced prostate cancer and 98% more likely to die from the disease. (The study showed no link between multivitamin use and the risk of localized prostate cancer.) Although the study suggests a need for caution, there's no need to throw away your vitamin bottles just yet. Upon closer examination, the study showed that men who took seven multivitamins a week, in keeping with the recommended daily amounts, did not have a higher risk of prostate cancer than men who took fewer or none at all. It was the men who exceeded seven multivitamins a week who were at increased risk.

All in all, the evidence that any food or nutrient plays a role in preventing cancer of the prostate remains sketchy. Further study is clearly needed before scientists can reach any firm conclusions. Taking a daily multivitamin is probably good insurance for all men. For the most part, it's a way to ensure that you get adequate daily amounts of vitamins without overdoing it. But there are three possible exceptions to be aware of. The first is selenium, since most multivitamins contain less than the 200 mcg that appears protective. Second, most multivitamins contain 400 international units (IU) of vitamin D, but many experts now recommend 600 to 800 IU a day. Finally, multivitamins don't contain any fish oil, but men with coronary artery disease, or with major risk factors for heart disease, may benefit from 1,000 mg of omega-3 fatty acids a day, and would be wise to take a supplement if they don't get that amount in their diet. For more on omega-3 fatty acids and prostate health, see "Complementary therapies for prostate cancer."

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Finasteride for prevention?

The Prostate Cancer Prevention Trial examined whether finasteride — a drug used to treat BPH (see "Alpha-reductase inhibitors") — may help prevent prostate cancer. This nationwide trial followed 18,000 healthy men. Finasteride appeared to help prevent prostate cancer: 18% of those who took 5 mg of finasteride a day developed the disease, compared with 24% of those who didn't take the drug.

Why might finasteride prevent prostate cancer? Researchers know that the drug interferes with the activity of an enzyme involved in male hormone metabolism. Because male hormones play a strong role in the development of prostate cancer, physicians hope that finasteride may block some of the cellular changes that lead to cancer. However, though finasteride appears to lower the risk of developing prostate cancer, studies haven't shown that finasteride reduces the number of deaths from prostate cancer. You can discuss the benefits and risks of taking finasteride with your doctor based on your own risk factors for prostate cancer (see "Are you at high risk for prostate cancer?").

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Review Date: 2008-03-01

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