FDA Consumer magazine May-June 2006 By Carol Rados Understanding Prostate Changes A Roundup of Treatments There is good evidence, according to the Centers for Disease Control and Prevention (CDC), that the current prostate specific antigen (PSA) test approved in 1986 by the Food and Drug Administration to screen for prostate cancer can detect the disease in its early stages. Evidence, however, is mixed and inconclusive about whether early detection actually saves lives. A study published in the Jan. 9, 2006, issue of the Archives of Internal Medicine found that screening with the PSA test does not cut down on deaths from the disease. Moreover, it is not clear whether the benefits of screening outweigh the risks of follow-up testing and cancer treatments. At the same time, evidence, such as a drop in the prostate cancer death rate--which some say could be due to improved treatments--suggests that early PSA testing may be saving lives. There are no definitive answers. According to the National Cancer Institute (NCI), other than skin cancer, prostate cancer is the most common form of cancer and the second leading cause of cancer-related deaths among men in the United States. But doctors' recommendations on screening for the disease vary. Some encourage annual screenings for men older than age 50; others recommend against routine screening. American Cancer Society (ACS) Screening Director Robert Smith, Ph.D., says that the January Archives of Internal Medicine study "isn't strong enough to say definitively that prostate cancer screening isn't valuable." The controversy, meanwhile, is contributing to a growing quandary for doctors and their patients: what's a man to do? Until there is more evidence and, perhaps, a scientific consensus of the screening benefits, most doctors and medical organizations, including the NCI, the ACS, and the CDC, agree that men should learn all they can about what is known and what is not known of the benefits and limitations of early detection and treatment for prostate cancer, so that they can make their own informed decisions. Cancer screening is just one health concern related to the prostate--a very important part of the male reproductive system. As men age, the prostate may become a source of troubling, often inconvenient problems that can, but don't necessarily, include cancer. And since the symptoms of some noncancerous prostate conditions can mimic cancer, many men who learn they have a problem often assume the worst. In general, growing older raises a man's risk for prostate problems, including cancer. For these reasons, it is important that men know and understand, in the earliest stages, the changes that can occur in the prostate and could, ultimately, affect their health. Understanding Prostate Changes The prostate is a walnut-shaped gland found only in men. It lies in front of the rectum, sits just below the bladder where urine is stored, and surrounds the tube that carries urine from the body (urethra). The gland functions as part of the male reproductive system by making a fluid that becomes part of semen, the white fluid that contains sperm. Three main problems can occur in the prostate gland: inflammation or infection, called prostatitis; enlargement, called benign prostatic hyperplasia (BPH); and cancer. Prostatitis is a clinical term used to describe a wide spectrum of disorders ranging from acute bacterial infection to chronic pain syndromes affecting the prostate, says Regina Alivisatos, M.D., a medical officer in the FDA's Center for Drug Evaluation and Research (CDER). There are four main types of prostate syndromes. Acute bacterial prostatitis, although the least common of the four types, is the easiest to diagnose and treat. This form, Alivisatos says, is caused by bacteria and comes on suddenly. "It's not something a doctor or patient would miss. It hurts, and there are a lot of white blood cells and bacteria in the urine," she says. Symptoms include chills and fever, pain in the lower back and genital area, and burning or painful urination. Chronic bacterial prostatitis also is caused by bacteria, but does not come on suddenly. The only symptom a man may have is bladder infections with the same bacteria that keep coming back. The cause may be a defect in the prostate that allows bacteria to collect in the urinary tract. Usually, the prostate is normal or somewhat tender on exam. Chronic (nonbacterial) prostatitis-chronic pelvic pain syndrome is the most common, but least understood, form of prostatitis. Found in men of any age from the late teens on, the symptoms go away and then return without warning, and may be inflammatory or noninflammatory. In the inflammatory form, urine, semen, and other fluids from the prostate show no evidence of a known infecting organism, but do contain the kinds of cells the body usually produces to fight infection. In the noninflammatory form, no evidence of inflammation, including infection-fighting cells, is present. Asymptomatic inflammatory prostatitis is the diagnosis when there are no symptoms, but the patient has infection-fighting cells in the semen. It is often found when a doctor is looking for causes of infertility or is testing for prostate cancer. According to the NCI, prostatitis is not contagious, and the vast majority of cases are not spread through sexual contact. Only a doctor can tell one form of prostatitis from another. BPH, or benign prostatic hyperplasia, is the second main problem that can occur in the prostate. "Benign" means "not cancerous"; "hyperplasia" means "too much growth." The result is that the prostate becomes enlarged. The gland tends to expand in an area that doesn't expand with it, causing pressure on the urethra, which can lead to urinary problems. The urge to urinate frequently, a weak urine flow, breaks in urine stream, and dribbling are all symptoms of an enlarged prostate. Because the prostate normally continues to grow as a boy matures to manhood, BPH is the most common prostate problem for men older than 50. Older men are at risk for prostate cancer as well, but it is much less common than BPH. A doctor will do a digital rectal exam (DRE) to check the size and condition of the prostate by inserting a gloved finger into the rectum. The doctor also may need to do special X-rays or scans to check the urethra, prostate, and bladder. BPH can lead to urinary problems like those with prostatitis. By age 60, many men have signs of BPH. By age 70, almost all men have some prostate enlargement. At its worst, BPH can lead to a weak bladder, bladder or kidney infections, complete blockage in the flow of urine, and kidney failure. It is true that some men with prostate cancer also have BPH, but the two conditions are not automatically linked. Most men with BPH do not develop prostate cancer. But because the early symptoms for both conditions could be the same, a doctor would need to evaluate them. Different prostate problems sometimes have similar symptoms, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). For example, one man with prostatitis and another with BPH may both have a frequent, urgent need to urinate. A man with BPH may have trouble beginning a stream of urine; another may have to urinate frequently at night. Or, a man in the early stages of prostate cancer may have no symptoms at all. But according to the NCI, one prostate change does not lead to another. For example, having prostatitis or an enlarged prostate does not increase the chance for prostate cancer. It is also possible to have more than one condition at a time. This confusing array of potential scenarios makes a case for the importance of all men, especially after age 45, to have a thorough medical exam that includes the PSA test and DRE every year. Adam S. Kibel, M.D., associate professor of urologic surgery at Washington University in St. Louis, says that in his practice, the most common concerns of men with prostate problems include the frequent need to urinate (particularly at night), the inability to delay urination (urgency), and the inability to urinate at all. "Getting up to go three, four, or even five times every night or having to get up in the middle of a movie--these things can interfere with a man's lifestyle," Kibel says. "And since all treatments [for prostate problems] have side effects, it's important for men to evaluate the effects of the different therapies so they can know what to expect." A Roundup of Treatments For men who are having prostate problems, the good news is that many new and effective treatments are available. For prostatitis, getting the right diagnosis of the exact type is key to getting the best treatment. George Benson, M.D., a medical reviewer in the FDA's CDER, says that prostatitis caused by an infection is treated with antibiotics, "but there are no drugs approved to treat chronic pelvic pain syndrome. This condition is often treated with anti-inflammatory drugs and analgesics," he says. Although BPH cannot be cured, FDA-approved drugs can often relieve its symptoms. Such drugs to treat BPH currently include two major classes. The 5 alpha-reductase inhibitors shrink the prostate gland and include Proscar (finasteride) and Avodart (dutasteride). These drugs work by blocking an enzyme that acts on the male hormone, testosterone, to boost organ growth. When the enzyme is blocked, growth slows down and the gland may shrink. This treatment may not produce a positive effect until after six to 12 months of treatment. It also works best for the larger prostate. Alpha-adrenergic receptor blockers, which work by blocking adrenergic nerve receptors in the lower urinary tract, basically help relax the smooth muscle of the prostate and bladder neck to relieve pressure and to improve urine flow. These drugs, which do not shrink the size of the prostate, include: Cardura (doxazosin), Flomax (tamsulosin), Hytrin (terazosin), and Uroxatral (alfuzosin). For many men, these alpha-blockers can improve urine flow and can reduce symptoms within days. Possible side effects include dizziness, headache, fatigue, and a lowering of blood pressure. Non-Surgical Treatments Because drug treatment is not effective in all cases, and different surgeries are often associated with serious complications, researchers have developed a number of procedures, including transurethral--accessing the affected area through the urethra--using FDA-approved or cleared medical devices to relieve BPH symptoms. These procedures are considered minimally invasive, non-surgical treatments: Transurethral microwave thermotherapy (TUMT). Uses microwaves sent through a catheter to heat and destroy excess prostate tissue. For most TUMT devices, a cooling system protects the portion of the urethra that goes through the prostate during the procedure. The TUMT procedure takes about one hour and can be an option for men who should not have major surgery because they have other medical problems. Microwave therapy does not cure BPH, but it reduces urinary frequency, urgency, straining, and intermittent flow. It does not completely correct the problem of incomplete emptying of the bladder. TUMT has limited long-term effects. Up to 40 percent of men treated may need re-treatment a few years later. Though rare, there have been cases reported of incontinence and impotence with this procedure. Although microwave thermotherapy has been demonstrated to be safe and effective, the FDA has been concerned in the past about unexpected procedure-related complications that occurred since these devices were marketed. Water-induced thermotherapy (WIT). Uses a device to treat urinary symptoms of BPH. The device uses hot water circulated through an inflated balloon catheter to heat the inside of the prostate, causing adjacent tissue to die. Over time, some tissue is either expelled through urine or absorbed internally. Surgical Treatments A number of devices with different modes of action have been cleared by the FDA to perform transurethral surgery that usually relieves any obstruction and incomplete emptying of the bladder. Less tissue is removed in these procedures, which is either ablated or vaporized, rather than cut. They are considered minimally invasive surgeries: Transurethral needle ablation (TUNA). Delivers low-level radio frequency energy through twin needles to burn away a well-defined area of the enlarged prostate. Transurethral vaporization of the prostate (TUVP). Uses electrical current to vaporize prostate tissue. Laser surgery. Uses side-firing laser fibers to vaporize obstructing prostate tissue. The doctor passes the laser fiber through the urethra into the prostate and then delivers several bursts of energy lasting 30 seconds to 60 seconds. The laser energy destroys prostate tissue and causes shrinkage. Laser surgery requires anesthesia and a hospital stay. One advantage of this laser evaporating surgery may be that it causes little blood loss. It also allows for a quicker recovery time. This procedure may not be effective on large prostates. Its long-term effectiveness is unknown. Transurethral resection of the prostate (TURP). Considered the gold standard for treating BPH, and accounts for 90 percent of all BPH surgeries. The doctor passes an instrument through the urethra and trims away extra prostate tissue. The tissue is sent to the lab to check for prostate cancer. This surgery requires anesthesia and a hospital stay. Recovery from TURP is much shorter than with open surgery, but TURP and other procedures for BPH remove only enough tissue to relieve urine blockage. Transurethral incision of the prostate (TUIP). Similar to TURP but, instead of removing tissue, widens the urethra by making a few small cuts in the bladder neck, where the urethra joins the bladder, and in the prostate gland itself, which relieves pressure without trimming away tissue. This procedure is often done on smaller prostates. The NIDDK says that although people believe that TUIP gives the same relief as TURP with less risk of side effects, its advantages and long-term side effects have not been clearly established. Open prostatectomy. Removes the prostate through a cut in the lower abdomen or between the anus and scrotum. This procedure is done only in rare cases when the prostate is very large with severe obstruction, or when other procedures can't be done. General or spinal anesthesia is used, and a catheter remains for up to seven days after the surgery. This surgery carries a higher risk of complications, such as incontinence and impotence, than medical treatment or less invasive surgeries. Removed tissue is sent to the lab to check for prostate cancer, and periodic follow-up is recommended. All of these procedures, whether less invasive or not, often require patients to wear a catheter for three to four days after surgery, and carry some risk of urinary incontinence and impotence. The CDRH says that the more invasive the procedure, the more risks are involved. Because all of these procedures involve the removal of some, but not all, of the prostate, regular follow-ups are necessary to watch for cancer. An alternative treatment that has become popular is an herbal pill--saw palmetto--used by millions of men in the United States to treat BPH. Saw palmetto, however, was recently found to have no effect in reducing the frequent urge to urinate or other annoying symptoms of an enlarged prostate. Published in the Feb. 9, 2006, New England Journal of Medicine, the yearlong study found that the plant extract was no more effective than inactive pills (placebos) in easing symptoms of BPH. Experts agree that the best protection against prostate problems is to have regular medical checkups that include a prostate exam. Prostate Cancer and the PSA Tests The third major problem that can occur in the prostate is cancer. It grows quietly for years, giving most men with the early disease no obvious symptoms. "It's a silent killer," says J. Brantley Thrasher, M.D., chairman of urology at the University of Kansas Medical Center in Kansas City, Kan., and spokesman for the American Urological Association (AUA). "So, most men with a nodule or elevated PSA aren't going to know it." That's why Thrasher and the AUA believe strongly in PSA testing. "It's an imperfect marker, but it's the best we've got." The FDA approved the PSA test for use in conjunction with a DRE to help detect prostate cancer in men 50 and older, and for monitoring prostate cancer patients after treatment. According to scientists in the FDA's Center for Devices and Radiological Health (CDRH), the finger examination can detect cancer in the form of a nodule or hardness, normally when it is about 50 percent advanced and not curable. PSA detects cancer when the finger exam appears normal in about 35 percent to 40 percent of cases, in the early stages of disease. Indeed, the NCI and the ACS agree that checking people for some cancers, such as breast and colon, even when they have no symptoms, can reduce deaths by finding tumors at an early stage, when they are easiest to treat. But when it comes to prostate cancer, the argument isn't so clear-cut. "Prostate cancer is generally a slow-growing cancer," says Cmdr. James P. Reeves, Ph.D., a medical device reviewer in the FDA's CDRH. "For those men who do not have slow-growing cancer that will threaten their lives, we do not have sufficient information that PSA or DRE testing prior to or after diagnosis would distinguish such men from those who will have cancer, but will not die from that cancer." So what's the harm in being tested? Reeves says that screening for prostate cancer sometimes finds tumors that wouldn't cause any problems if left untreated. Many professional medical organizations agree. But there's no good way at this time to tell which cancers need treating and which don't. Therefore, many men who are diagnosed with prostate cancer likely will be treated, but also may experience unnecessary and harmful side effects that could lower their quality of life. About 15 percent to 50 percent of men treated for prostate cancer by surgery, radiation therapy, or hormonal therapy will have urinary incontinence and sexual impotence, and in extremely rare cases, scarring of the intestine. "These percentages indicate that there is a risk for significant harm from over-treatment of prostate cancer," Reeves says. "Is the cure worse than the disease, especially if the cancer is not significant enough to threaten a man's life over 10 to 15 years of remaining life expectancy?" There are some men who have ample reason to choose the cure. "My grandfather and my father had prostate cancer," says 54-year-old David Glunt from St. Louis. "And at 51 years old, I wasn't taking any chances." Glunt's younger brother tested positive for prostate cancer four years ago; Glunt tested negative. "But I was betting all along that I would get it," he says. A year later, he did. Speaking on behalf of the AUA, Thrasher says that while a more specific and sensitive marker is needed, questioning the validity of early screening puts men at risk. "Physicians should discuss the risks and benefits of prostate cancer screening on a yearly basis with men 50 to 75 years of age, and earlier if they are African-American or have a family history of prostate cancer," Thrasher says. Screening, he adds, should include both a PSA test and DRE. Because so much remains unknown about how to interpret the PSA test, its ability to discriminate between cancer and noncancerous conditions, and the best course of action if the PSA is high, the magnitude of the test's potential risks and benefits also is unknown. Still, Kibel adds, "the PSA controversy should not stop men from discussing being tested with their doctors." In its early stages, prostate cancer stays in the prostate and is not life-threatening. But without treatment, cancer eventually spreads to other parts of the body, often resulting in death. Doctors have several ways to treat prostate cancer. The choice depends on many factors, such as whether or not the cancer has spread beyond the prostate, the patient's age and general health, and how the patient feels about the treatment options and their side effects. According to both the NCI and the ACS, approaches to treatment include: watchful waiting to see whether the cancer is growing slowly and not causing symptoms; surgery to remove the entire prostate and surrounding tissues; and internal and external radiation therapy, both of which use high-energy rays to kill cancer cells and shrink tumors. Hormone therapy and chemotherapy drugs are approved to treat the various advanced stages of cancer. The gold standard for treating early, localized prostate cancer is radical retropubic prostatectomy. The whole prostate and seminal vesicles are removed. At Johns Hopkins Hospital in Baltimore, the surgery has improved over the years with the development of a nerve-sparing procedure. This procedure, says the CDRH, in most cases, avoids sexual impotence. The same technique has been used in the last decade by many urologists in the United States and throughout the world. Computer- or robot-assisted surgery was cleared by the FDA in 2005 for use in all urological procedures, including the removal of the prostate (radical prostatectomy) because of cancer. Even though the prostate is surrounded by nerves and muscles that affect urinary, rectal, and sexual functions, doctors say that improved vision and flexibility of the instruments allow for magnification of the prostate during this procedure. "It's too early to tell if this will equate to more precision and better outcomes," adds Thrasher. Regular checkups are important even for men who have had surgery. BPH surgery does not protect a man against prostate cancer, because the prostate is not completely removed. Research is under way to evaluate new approaches to finding even more effective treatments for prostate and urinary disorders. -------------------------------------------------------------------------------- The Science Behind Prostate Specific Antigen Prostate specific antigen (PSA) is a substance made by the prostate gland. Although the substance is mostly found in semen, a small amount is also present in the blood. According to the American Cancer Society, most men have levels under 4 nanograms per milliliter of blood (ng/ml). When prostate cancer develops, the PSA level usually goes above 4ng/ml but in some cases, the cancer can be present at levels lower than 4. A PSA rise does not automatically mean cancer. PSA also rises when the prostate is enlarged because of benign prostatic hyperplasia, or BPH, and sometimes with prostatitis. If the level is borderline range between 4ng/ml and 10ng/ml, a man has about a 25 percent to 35 percent chance of having prostate cancer. PSA higher than 10ng/ml could mean between a 40 percent and 50 percent chance for cancer, and the risk increases further as the PSA level increases. PSA is an ideal marker for prostate cancer because it is basically restricted to prostate cells. Most PSA tests measure "total PSA," or the amount that is bound to blood proteins. But some tests measure not only total PSA, but another component called free PSA, which floats unbound in the blood. Free PSA above 25 percent is a stronger indication that cancer is not present. Comparing the two helps doctors rule out cancer in men whose PSA is mildly elevated from other causes. The benefits of screening for prostate cancer are still being studied. Scientists are researching ways to distinguish between cancerous and noncancerous conditions, those that are slow-growing and fast-growing, and potentially lethal cancers through new PSA methods and other tumor markers. The National Cancer Insitute and other medical organizations are conducting the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO Trial, to determine whether certain screening tests reduce the number of deaths from these cancers. The PSA and DRE tests are being studied to see whether yearly screening will decrease a man's chance of dying from prostate cancer. For More Information Food and Drug Administration

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