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Special Health Reports


2011 Annual Report on Prostate Diseases

Covering advances in the diagnosis and treatment of prostate cancer, BPH, erectile dysfunction, prostatitis, and related conditions

5. Prostate cancer

What you need to know at every stage of the disease

Prostate cancer accounts for about 11% of cancer-related deaths in men. But many prostate cancers are slow-growing and may never reach the point of becoming dangerous. The hard part is to determine which cancers are which, because there are no straightforward diagnostic tests. Prostate cancer can also be difficult to diagnose because it has no dramatic warning signs and progresses so slowly. But that slow growth can be beneficial: unlike cancers that develop rapidly, prostate cancer usually gives you plenty of time to make treatment decisions — and as surprising as this may seem, those decisions might mean no treatment at all.

Aside from skin cancer, prostate cancer is the most common cancer in American men. The American Cancer Society estimates that 217,730 men, mostly over age 65, were diagnosed with the disease in 2010. After a sharp rise between 1988 and 1992, the incidence of prostate cancer leveled off. Between 2000 and 2006, the incidence fell by 2.4% per year. Mortality trends have been similar. After leveling off between 1991 and 1994, prostate cancer death rates fell by 4.1% per year. In 2010, approximately 32,050 men died of the disease.

Those and other statistics — the fact that one in six men will be diagnosed with prostate cancer during his lifetime, for example — may sound staggering. But keep in mind that only one in 36 will die of this disease. Most men who have the disease would never have even known it was there if a biopsy hadn't been done. Autopsy studies of men who died of other causes have found that 70% to 90% had some degree of prostate cancer by age 80, but they experienced no ill effects. So, indeed, many prostate cancers are slow-growing.

So why the increase in incidence between 1988 and 1992, and the subsequent decline in deaths? Many factors may account for these shifts. 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.

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 observational investigations 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 cancer. 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.

What causes prostate cancer?

No one knows precisely what causes the disease, but researchers are studying cells to learn what damages their DNA and why some cells, once damaged, can repair themselves while others continue down the path toward prostate cancer. Scientists do know that a person's genes play a role. For example, certain genes (oncogenes) encourage cells to grow and divide. Other genes (tumor suppressor genes) can tell cells to slow their growth and when to die. Like lights, these genes have switches. If the switch that controls an oncogene is stuck in the "on" position, or if the switch for a tumor suppressor gene is stuck in the "off" position, cancer can grow.

DNA mutations may be inherited or may occur during a person's lifetime. For example, an inherited gene called HPC1 seems to account for a small percentage of prostate cancer cases. Men with changes in their BRCA1 and BRCA2 genes — genes that when mutated can cause breast cancer in women — also seem to have a higher risk of prostate cancer. But experts estimate that inherited mutations cause only about 5% to 10% of prostate cancers.

DNA mutations that occur during a person's lifetime may simply be random mistakes, errors made in copying the DNA when a cell divides. Researchers aren't sure whether lifestyle factors, such as diet, or environmental factors, such as toxic chemical exposure, might speed up cell division, which could cause more copying errors. Perhaps these factors cause mutations on their own.

Researchers have also suggested that certain hormones may be to blame. For example, some studies have shown that men with high levels of insulin-like growth factor 1 have a higher chance of developing prostate cancer than men with normal levels of the hormone.

Regardless of the exact cause, researchers have identified several factors that increase a man's risk of developing prostate cancer:

  • Age. The risk of prostate cancer increases with age. The average onset is at age 70, and about 98% of cases occur in men over age 55.

  • Family history. 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.

  • Race. African American men have the highest rate of prostate cancer. Asian American and Hispanic men are less likely to have the disease than white men. 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 men of other races. Another possibility is a particular variation in the gene involved in metabolizing testosterone. This genetic variant seems to occur more often in African Americans than in men of other races.

  • Nationality. Men in North America, northwestern European countries, Australia, and the Caribbean are more likely to develop prostate cancer than men in Africa, Asia, and Central and South America. Genetic factors, as well as intensive screening efforts in some countries, may account for a bit of the disparity. But environmental and lifestyle factors, such as diet, may be responsible for the differences, too.

  • Diet. How diet influences risk isn't entirely clear, but studies have found associations between prostate cancer and the consumption of certain types of foods. For example, men who eat a lot of red meat or high-fat dairy products seem to have a higher risk of the disease. Some studies have also found that high levels of calcium (much more than what's in the average diet) seem to raise the risk. That's why experts generally recommend a diet high in fruits and vegetables and low in saturated fat.

Researchers have examined other factors that might play a role in the development of prostate cancer — sexually transmitted diseases, prostatitis, and exercise, to name a few — but study findings have been inconsistent, and no firm conclusions have been drawn.* Early studies indicated that having a vasectomy might increase risk, but subsequent research has disputed this finding (see "Vasectomies: Are they hazardous?").

*Editor's note: Web EXTRA! To learn how sexual activity might influence prostate cancer risk, visit www.health.harvard.edu/prostateexclusive and enter the access code PA2011.

Can prostate cancer be prevented?

The cause of prostate cancer is unknown, which means it's hard to suggest preventive measures. Research to date indicates that taking certain medications, a strategy called chemoprevention, may be promising. Dietary changes may also help, but evidence for this recommendation remains lacking.

Chemoprevention

Clinical trials have found that two drugs commonly used to treat benign prostatic hyperplasia (BPH) — finasteride (Proscar, generic) and dutasteride (Avodart) — may help prevent prostate cancer (see "5-alpha-reductase inhibitors"). The nationwide Prostate Cancer Prevention Trial followed 18,882 healthy men, ages 55 and older, who were randomly assigned to take either 5 milligrams (mg) of finasteride or a placebo daily for seven years. Initial results showed that among those who took finasteride, the prevalence of prostate cancer fell by 24.8% (see "Finasteride findings"). But the study also indicated that the drug increased the risk of developing aggressive prostate cancer in some men.

Finasteride findings

Redman MW, Tangen CM, Goodman PJ, et al. Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach. Cancer Prevention Research 2008;1:174–81. PMID: 19138953.

Thompson IM, Goodman PJ, Tangen CM, et al. The Influence of Finasteride on the Development of Prostate Cancer. New England Journal of Medicine 2003;349:215–24. PMID: 12824459.

A more recent analysis and an assessment of biopsy tissue collected as part of the trial may have resolved that concern. In addition to reducing overall prostate cancer risk by 25% to 30%, finasteride showed no tendency to increase the rate of aggressive tumors. In fact, it apparently decreased the rate of aggressive tumors by 27%. The researchers said that because finasteride shrinks the prostate, it may be easier to find cancer in a biopsy. However, many experts remain unconvinced.

An international trial of dutasteride found that the drug may reduce the chances of developing prostate cancer in men at high risk for the disease. In this trial, dubbed REDUCE, researchers enrolled more than 8,100 men ages 50 to 75 who had elevated prostate-specific antigen (PSA) levels (2.5 to 10 ng/ml) but had a negative biopsy within the previous six months. The participants were randomly assigned to take 0.5 mg of dutasteride daily or a placebo daily. After four years, the men taking dutasteride had reduced their chances of being diagnosed with prostate cancer by almost 23% compared with those taking the placebo. And unlike the initial finasteride findings, the two groups showed no significant difference in the number of high-grade tumors, defined as those with Gleason scores of 7 to 10 (see "Dutasteride findings").

Dutasteride findings

Andriole GL, Bostwick DG, Brawley OW, et al. Effect of Dutasteride on the Risk of Prostate Cancer. New England Journal of Medicine 2010;362:1192–202. PMID: 20357281.

What prompted researchers to study these drugs in the first place? Their thinking was based on two observations:

  1. Male hormones, or androgens, drive the development of prostate cancer. Two common androgens are testosterone and dihydrotestosterone (DHT).

  2. Men who are deficient in an enzyme called 5-alpha-reductase type 2 don't develop BPH or prostate cancer. Without 5-alpha-reductase type 2, testosterone can't be converted into DHT, which promotes prostate growth.

Because these drugs tamp down 5-alpha-reductase type 2, researchers hypothesized that they would lower DHT levels and help prevent prostate cancer.

Although studies suggest that men can cut their risk of prostate cancer by taking finasteride or dutasteride, keep in mind that studies haven't shown that the drugs reduce the number of deaths from the disease. And even though the drugs may reduce risk, they don't eliminate it. The drugs may also cause side effects, such as a decrease in sex drive, problems achieving an erection, and a drop in semen volume. No one knows the long-term effects of taking finasteride or dutasteride. As a result, many doctors are reluctant to prescribe them (see "Ask a doctor," "Hesitation on chemoprevention," and "Advisory panel rejects BPH drugs for cancer prevention"). But if you have a high risk of prostate cancer or an elevated PSA level and show no signs of disease, you might want to ask your doctor about the benefits and risks of taking finasteride or dutasteride.

Ask a doctor

Do you prescribe finasteride or dutasteride to patients for the prevention of prostate cancer? Three physicians reply:

Although I frequently prescribe finasteride and dutasteride to treat symptomatic BPH in men with substantially enlarged prostates, I do not recommend either drug to prevent prostate cancer.

To understand why, remember that prostate cancer is a very unusual disease. Although some cases are aggressive — and even lethal — most are slow-growing and even harmless. It's true that both finasteride and dutasteride reduce the overall risk of prostate cancer. Unfortunately, while the drugs appear to prevent the slow-growing forms of the disease, they have little if any effect on the nasty forms of prostate cancer. In fact, the landmark 2003 study on finasteride for prevention reported that the drug actually increases the risk of developing aggressive prostate cancer.

Furthermore, both drugs are expensive, and they need to be taken daily for many years. Both can have troublesome side effects, including sexual dysfunction and enlarged breasts. Because they lower PSA levels, they can also complicate PSA testing for men who choose to be screened for prostate cancer.

What can a man do to reduce his risk of the disease? The best approach is a good diet — less red meat and saturated fat, and more fish, whole grains, and vegetables — and enough exercise to burn off excess body fat. Not coincidentally, it's a program that also has proven benefit against heart disease, hypertension, stroke, and diabetes.

— Harvey Simon, M.D.
Primary Care Internist, Massachusetts General Hospital

I routinely recommend these medications to treat symptoms related to an enlarged prostate, but I prescribe them very infrequently for the specific purpose of reducing prostate cancer risk. Although both the PCPT and REDUCE demonstrated a lower cancer rate in men taking these medications compared with men taking placebo, the reduction was noted only in men with low-grade (Gleason 6 or less) cancers. Since the rates of Gleason 7 and higher cancers were not reduced, and since these are the tumors that are more likely to cause harm, I am far from convinced that this treatment will have a significant benefit to men. It is important to note that neither study found a difference in mortality due to their relatively short duration, so it remains an open question whether these medications truly affect prostate cancer in a meaningful way.

In addition, the sexual side effects of these medications can be troublesome. We tend to assume that changes in sexual desire or performance that are caused by medications should go away if a man stops taking the medication, yet I have seen a disturbing number of cases where men insisted that they have never been the same afterward.

I am most likely to consider treatment in men with an elevated PSA who have had multiple negative biopsies and are anxious about their risk of eventually being diagnosed with cancer. Psychologically, some of these men seem quite relieved when their PSA is reduced, even though they understand that the reduced PSA is caused by the medicine, and is therefore largely artificial.

— Abraham Morgentaler, M.D.
Urologic Surgeon, Men's Health Boston

Although the initial reports on finasteride and dutasteride seem to represent a breakthrough, closer analyses have caused serious doubts with regard to the validity and utility of this information. For example, neither drug significantly reduced the risk of prostate cancer among men who were followed closely and underwent a biopsy because of an elevated PSA or abnormal digital rectal exam, a so-called for-cause biopsy. In the clinical world, these are precisely the cases we would hope to prevent.

Secondly, there was no reduction in high-grade tumors with either drug compared to placebo. Some experts have suggested that these drugs do not prevent prostate cancer but rather only delay the progression of low-grade disease (but not progression of high-grade disease). Longer follow-up time would be required to test that very plausible hypothesis. Supporting this observation, an analysis of the Finnish prostate cancer screening trial showed that there was no significant decrease in the incidence of prostate cancer among men in the screening group who were taking finasteride as compared to men taking placebo.

Finally, these 5-alpha-reductase inhibitors are second-line drugs for bladder symptoms (second to alpha blockers for symptoms of bladder obstruction), so their use is not guaranteed to improve symptoms. More worrisome, however, are their potential side effects — decreased libido, erectile dysfunction, decreased semen volume, and enlarged breasts — all of which occur at a much higher rate in my practice than is listed in the literature.

For these and many more reasons, I do not prescribe finasteride or dutasteride for the prevention of prostate cancer. Chemoprevention is an interesting idea, but it needs further development.

— William C. DeWolf, M.D.
Chief, Division of Urology, Beth Israel Deaconess Medical Center

Dietary changes

The science of food and cancer prevention is a moving target that, so far, hasn't produced clear-cut advice for prostate cancer prevention. One of the more promising menu items is fish. It's not clear why fish may be protective, but one theory is that the omega-3 fatty acids in fatty fish like salmon may inhibit a particular molecular pathway involved in prostate cancer development. This speculation aside, two large prospective studies found that men who ate moderate to high amounts of fish were less likely to develop prostate cancer or die from it compared with men who did not eat fish. But a 2008 paper reported that eating fish was unrelated to prostate cancer incidence.

Fish may also slow progression of the disease. A 2006 study found that men who ate the most fish after a prostate cancer diagnosis were 27% less likely to have their cancer progress than men who consumed the least (see "Benefits of fish").

Benefits of fish

Augustsson K, Michaud DS, Rimm EB, et al. A Prospective Study of Intake of Fish and Marine Fatty Acids and Prostate Cancer. Cancer Epidemiology, Biomarkers and Prevention 2003;12:64–7. PMID: 12540506.

Chan JM, Holick CN, Leitzmann MF, et al. Diet After Diagnosis and the Risk of Prostate Cancer Progression, Recurrence, and Death (United States). Cancer Causes and Control 2006;17:199–208. PMID: 16425098.

Chavarro JE, Stampfer MJ, Hall MN, et al. A 22-Year Prospective Study of Fish Intake in Relation to Prostate Cancer Incidence and Mortality. American Journal of Clinical Nutrition 2008;88:1297–303. PMID: 18996866.

Terry P, Lichtenstein P, Feychting M, et al. Fatty Fish Consumption and Risk of Prostate Cancer. Lancet 2001;357:1764–66. PMID: 11403817.

Although the evidence is mixed, some studies suggest that a diet rich in fruits and vegetables may reduce risk, too. Carotenoids, which occur naturally in plants, have antioxidant properties. One study reported that men with higher blood levels of particular carotenoids — lutein, beta cryptoxanthin, and zeaxanthin — had a 70% to 80% reduction in risk of prostate cancer. But a randomized clinical trial found that men who took beta carotene supplements had an increased risk of prostate cancer if they already had high blood levels of this antioxidant (see "Diet's role").

Diet's role

Chan JM, Gann PH, Giovannucci EL. Role of Diet in Prostate Cancer Development and Progression. Journal of Clinical Oncology 2005;23:8152–60. PMID: 16278466.

In 1995, a large epidemiologic study by Harvard researchers found that men who ate at least 10 servings a week of tomato-based foods reduced their risk for prostate cancer 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 in tomatoes and tomato products. However, a 2007 review by the FDA 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 (see "Tomatoes").

Tomatoes

Giovannucci E, Rimm EB, Liu Y, et al. A Prospective Study of Tomato Products, Lycopene, and Prostate Cancer Risk. Journal of the National Cancer Institute 2002;94(5):391–98. PMID: 11880478.

Kavanaugh CJ, Trumbo PR, Ellwood KC. The U.S. Food and Drug Administration's Evidence-Based Review for Qualified Health Claims: Tomatoes, Lycopene, and Cancer. Journal of the National Cancer Institute 2007;99:1074–85. PMID: 17623802.

Kirsh VA, Mayne ST, Peters U, et al. A Prospective Study of Lycopene and Tomato Product Intake and Risk of Prostate Cancer. Cancer Epidemiology, Biomarkers and Prevention 2006;15:92–98. PMID: 16434593.

Other foods, such as soy products and pomegranate juice, have been touted as cancer-fighters, but here, too, evidence is limited (see "Foods for prevention?").

Foods for prevention?

Trottier G, Boström PJ, Lawrentschuk N, Fleshner NE. Nutraceuticals and Prostate Cancer Prevention: A Current Review. Nature Reviews Urology 2010;7:21–30. PMID: 19997071.

All of this begs the question, "What about vitamins?" A study published in 2007 found that not only do vitamins — in this case, multivitamins — not help, but they may cause harm. The report, published in TheJournal 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.) Upon closer examination, however, 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 (see "Multivitamin findings").

Multivitamin findings

Lawson KA, Wright ME, Subar A, et al. Multivitamin Use and Risk of Prostate Cancer in the National Institutes of Health–AARP Diet and Health Study. Journal of the National Cancer Institute 2007;99:754–64. PMID: 17505071.

Even so, many experts, including several on the advisory board for this publication, recommend that men discontinue taking multivitamins and vitamin supplements (except vitamin D supplements) unless they were prescribed by a physician for a specific condition.

Hesitation on chemoprevention

Although the 2003 Prostate Cancer Prevention Trial (PCPT) showed a 25% reduced risk of prostate cancer among men who took finasteride, doctors have not been prescribing the drug for prostate cancer prevention, a 2010 study found. The study surveyed 599 urologists and primary care providers within the Veterans Health Administration about their prescribing patterns from 2000 to 2005.

Although the number of men taking finasteride increased during the six-year period, publication of the PCPT results had little impact. Among doctors who reported changing their prescribing habits, fewer than 2% said they were influenced by the PCPT. Also of note, 64% of urologists and 80% of primary care providers said they never prescribe finasteride to prevent prostate cancer. Asked why, more than half of urologists said they were concerned about inducing high-grade tumors, while about half of primary care providers didn't know the drug could be used for chemoprevention.

The majority of urologists and many of the primary care providers who did prescribe finasteride for disease prevention reserved it for patients at high risk for prostate cancer, although they were more likely to prescribe it for men with moderate to severe BPH than men with known risk factors for prostate cancer. So even when the doctors were aware of the benefits, they were reluctant to prescribe finasteride to otherwise healthy men because of the potential risks, the researchers concluded.

Source: Hamilton RJ, Kahwati LC, Kinsinger LS. Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer Epidemiology, Biomarkers and Prevention 2010;19:2164–71. PMID: 20699373.

How is prostate cancer detected?

Most men don't exhibit any symptoms of prostate cancer (see "Symptoms of prostate cancer") in the initial stages of the disease. That's why for years many physicians and health organizations encouraged men to get regular prostate checkups, including a digital rectal examination and PSA test. They argued that these screening techniques offered the best hope for discovering and treating cancer early, before it spreads to other parts of the body. That approach wasn't perfect, but many experts believed it saved lives.

Symptoms of prostate cancer

Many men with prostate cancer have no symptoms. But because the prostate gland is enlarged both in cancer 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 or ejaculate

  • frequent pain or stiffness in your lower back, hips, or upper thighs.

But with the publication of several studies, the benefits of early screening with the PSA test are less clear, and physicians and organizations are rethinking their original stance on screening (see "Studies question benefit of PSA screening" and "Positions on PSA testing"). 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 decisions. 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, with higher scores often triggering a biopsy. 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 25% chance of having prostate cancer; if his PSA is greater than 10, the likelihood increases to more than 50%. 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 ng/ml). That's almost the same rate of cancer as found in men with PSAs above the normal limit (4.1–10 ng/ml). However, discriminating between a normal and an abnormal PSA below 4 ng/ml is very difficult.

Many physicians now rely on measures known as serial PSA or 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 level 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 ng/ml might be considered normal for a 73-year-old man, whereas a PSA of 3.9 ng/ml 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 ng/ml 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.

In many cases, a suspicious PSA test will lead to additional procedures (ultrasound and biopsies) and possibly to major surgery or radiation. Some men with prostate cancer may be treated needlessly — and suffer from complications of treatment, such as impotence and incontinence. That's why it's extremely important for you to understand the uncertainties and decisions you will face before choosing to have your PSA level measured. And if you decide to have a PSA test, keep in mind that PSA levels can vary for reasons unrelated to cancer. Before acting on a surprisingly high PSA, consider repeating the test in a month or two to confirm the result.

Positions on PSA testing

No major medical organization recommends routine prostate cancer screening for all men. Instead, organizations suggest that men make informed decisions about screening in concert with their doctors. Here's what several organizations recommend:

  • The American Cancer Society recommends that men who are in relatively good health and likely to live at least 10 years talk with their doctor, beginning at age 50, about the risks and potential benefits of screening. Men at high risk — African Americans and men who have a father, brother, or son diagnosed with prostate cancer before age 65 — should talk with their doctor, beginning at age 45, about screening. Men at higher risk — those with multiple family members diagnosed with the disease before age 65 — should start even earlier, at age 40. For men who choose to be screened, a digital rectal examination is optional.

  • The American College of Physicians, the National Cancer Institute, the American Academy of Family Physicians, and the American College of Preventive Medicine also recommend that doctors run through the potential benefits and drawbacks of early prostate cancer detection with their patients to help them make informed decisions about whether to be screened.

  • The American Urological Association (AUA) recommends that doctors offer PSA testing to men ages 40 and older who have a life expectancy of at least 10 years. The goal is to provide a baseline reading for comparison if additional tests are done in the future. Rather than setting a single PSA level above which a biopsy should be done, the AUA now says the decision to biopsy should take into account multiple factors, including free and total PSA values, PSA velocity, and PSA density; the patient's age, family history, and race or ethnicity; results of any previous biopsies; and the patient's other medical conditions.

  • The Centers for Disease Control and Prevention and other federal agencies follow the guidelines set forth by the U.S. Preventive Services Task Force (USPSTF). The USPSTF has concluded that there is not enough evidence to determine whether prostate cancer screening in men younger than 75 is beneficial and has recommended against screening in men over 75. The USPSTF suggests that men discuss the risks and potential benefits of screening with their doctor.

The next step in diagnosis

If your PSA level is elevated, doctors will generally suggest having a biopsy, which is guided with transrectal ultrasound (see "Biopsy" and "Ultrasound" for details). 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 (see "How fast is it growing?" below) and lower PSA levels. In some situations, however, doctors use them to help assign a stage to the cancer.

What stage is it?

Ultimately, the prognosis and decisions about treatment depend on staging. A staging system is a common way of describing how far the cancer has progressed. There are different staging systems for prostate cancer, but the most widely used one is the TNM system, short for tumor-node-metastasis (see Figure 9). It describes the extent of the primary tumor (T category), whether the cancer has spread to nearby lymph nodes (N category), and whether it has spread to distant sites (M category).

A man's prognosis depends on the stage of the cancer when it's diagnosed. If it's detected when it's still confined to the prostate, as is the case for most prostate cancers today, the five-year prostate cancer–specific survival rate is nearly 100%. (The patient may die of other causes, however.) If the cancer has already spread to distant lymph nodes, bone, or other organs when it is diagnosed, the five-year survival rate is 31%.

Figure 9: Stages of prostate cancer

Stage T1

Stages of Prostate Cancer

Your doctor can't feel these tumors during a DRE or see them with an imaging test such as a transrectal ultrasound.

  • T1a: Tumor is found incidentally during treatment for BPH; less than 5% of the tissue removed is cancerous.

  • T1b: Like T1a, but more than 5% of the tissue removed is cancerous.

  • T1c (not shown): Detected when an elevated PSA leads to a needle biopsy.

Stage T2

Stages of Prostate Cancer

These cancers can be felt during a DRE and seem confined to the prostate.

  • T2a: The cancer fills less than half of one side (left or right) of the prostate.

  • T2b: Like T2a, but the cancer fills more than half of one side (left or right) of the prostate.

  • T2c (not shown): Like T2a, but cancer is detected in both sides (left and right) of the prostate.

Stage T3

Stages of Prostate Cancer

These cancers have broken through the prostate's fibrous capsule.

  • T3a: The cancer extends outside the prostate, but has not spread to the seminal vesicles.

  • T3b: The cancer has spread to the seminal vesicles.

Stage T4 (not shown)

Like T3 disease, but the cancer invades other nearby structures, such as the rectum or the muscle that helps control urination.

Stages N and M

Stages of Prostate Cancer

These cancers have metastasized to the pelvic lymph nodes (N1) or to other parts of the body (M1). Cancers that have spread to distant lymph nodes are classified as M1a, while cancers that have spread to the bones are M1b. Cancers that have spread to other sites, such as the lungs, but not the bones, are classified as M1c.

How fast is it growing?

Doctors 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.

Tumors often consist of multiple types of cells (see Figure 10). 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, or pattern, is 1. If they have changed to look more like cancer cells and are therefore likely to spread quickly, the pattern is 5, the highest rating. The same grading process is repeated for the second most common type of cell in the biopsy specimen.

Figure 10: Gleason patterns

Gleason patterns

Well differentiated

  1. Cells are small, of fairly uniform shape, and tightly packed together.

  2. Cells display more varied and irregular shapes and are loosely packed.

Moderately differentiated

  1. Cells are even more irregular in size and shape and are more dispersed; some cells are fused, and cell borders are less distinct.

Poorly differentiated

  1. Many cells are fused into irregular masses; some cells (those darkly shaded) have begun to invade the connective tissue that separates cells.

  2. Most of the tumor consists of irregular masses that have invaded the connective tissue.

Combining the two grades — 4+3, for example — yields a Gleason score, which can range from 2 to 10. The higher the score, 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.

Once the TNM category, PSA level, and Gleason score have been determined, physicians consider that information and assign a stage grouping. The overall stage is expressed in Roman numerals from stage I (the least advanced) to stage IV (the most advanced). This helps physicians evaluate the probable course of the illness and the best possible approaches to treatment.

Statistical tools called risk calculators, or nomograms, offer help in understanding the nature of a particular tumor (indolent vs. aggressive) and guidance in making treatment decisions. Two such tools can be accessed online. One is on the European Association of Urology's Web site, www.uroweb.org. The other, from Memorial Sloan-Kettering Cancer Center, is available at www.mskcc.org/mskcc/html/10088.cfm. Note that risk calculators have limitations and should be used in consultation with a physician who can offer advice on treatment decisions.

Ask a doctor

Would you screen a 75-year-old man whose brother died of prostate cancer even though the U.S. Preventive Services Task Force guidelines suggest that a man this age no longer needs to be screened for the disease? Two physicians respond:

There is no right or wrong answer. Guidelines help doctors make decisions. They do not mandate what should be done in any specific situation. If this man were my patient, I would need additional information:

  1. Is he in good general health (no conditions that would likely cause him severe disability or death within the next 10 years)?

  2. Is he of African descent?

  3. If not of African descent, was his brother under age 60 when he was diagnosed with prostate cancer?

If the answer to question 1 is no, then I would advise against screening. If the answer to question 1 is yes and the answer to question 2 or 3 is yes, I would discuss the pros and cons of prostate cancer screening with him.

Even if his brother died of prostate cancer at a younger age and/or he is African American, he is still more likely to die from some cause other than prostate cancer. But his risk of aggressive prostate cancer is probably higher than average. If he wanted screening despite all the possible complications of screening and prostate cancer treatment, then I would not hesitate to order a PSA blood test and do a digital rectal examination.

— Howard LeWine, M.D.
General Internist, Brigham and Women's Hospital

I would break this question into two pieces: what is this man's risk of developing a clinically important prostate cancer over the next 10 to 15 years, and how much does having a brother who died of prostate cancer increase that risk?

Having a first-degree relative with prostate cancer nearly doubles a man's risk of prostate cancer. Although I am not sure this is the case, I would assume that having a first-degree relative who died from prostate cancer (and who presumably had a higher-stage cancer) would increase the risk further. If this particular 75-year-old man also has other risk factors for prostate cancer, such as being of African extraction, that would increase the risk further.

So, I would probably screen such a 75-year-old man, even though his risk of developing a fatal prostate cancer is still quite low. Granted, at his age other diseases might be more likely to cause his death, but he still has an increased risk of suffering from prostate cancer. I might be able to prevent that suffering by finding the cancer at an early stage.

— Anthony Komaroff, M.D.
General Internist, Brigham and Women's Hospital

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. You might even opt for no treatment at all.

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 today that figure nears 100%. And now more than three-quarters of all men diagnosed with prostate cancer survive at least 15 years. This impressive change is partly due to earlier and more frequent diagnosis based on widespread PSA screening, but it also reflects improved treatment.

Although about 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 as long as men who didn't have prostate cancer (see "Surviving with early-stage 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; high-intensity focused ultrasound (still considered experimental in the United States); 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, no one treatment can be proved to be 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. 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.

Surviving with early-stage prostate cancer

Albertsen PC, Fryback DG, Storer BE, et al. Long-Term Survival Among Men with Conservatively Treated Localized Prostate Cancer. Journal of the American Medical Association 1995;274:626–31. PMID: 7637143.

Active surveillance

Some men diagnosed with prostate cancer need no treatment; for example, men with small, slowly progressing stage T1 cancers with Gleason scores of 5 or 6 who also have another serious medical condition, or men with a life expectancy of less than 10 years. Many older men, especially those 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 men, doing nothing may be the most sensible option. At the other end of the spectrum are younger men — say, those ages 55 to 60, with an aggressive cancer in the early stages and a family history of prostate cancer. Virtually all doctors will agree that these men require treatment.

But today, a significant number of men fall into a gray zone, where the decision of whether or not to treat isn't clear-cut. These men can consider pursuing active surveillance, a strategy that involves monitoring the cancer closely and choosing to undergo treatment when and if it advances or shows evidence of increasing activity, such as a sharp rise in PSA levels or a higher Gleason score on a repeat biopsy (see "Active surveillance vs. watchful waiting"). That's why active surveillance is sometimes called active monitoring or deferred treatment.

Active surveillance vs. watchful waiting

In the past, doctors used the term "watchful waiting" to describe any strategy that involved following a prostate tumor to see if it worsened, whether or not there was a set schedule of testing. And while some practitioners of watchful waiting eventually had their cancer treated, others had no intention of doing so. Today, patients who monitor their cancer closely and plan to have treatment when its activity increases are said to be pursuing "active surveillance." Many doctors now use the terms "watchful waiting" and "observation" when patients don't plan to have treatment.

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. Any man who tends to worry a great deal might prefer treatment over waiting and worrying, even if his tumor is slow-growing. And treatment might also make sense for men suffering from benign prostate enlargement (see "When active surveillance may be less than ideal").

The whole concept of active surveillance stemmed from a 1994 article in The Journal of the American Medical Association (see "Origins of active surveillance"). Since then, several research groups and medical centers have developed specific criteria to better differentiate men diagnosed with early-stage prostate cancer who can pursue active surveillance from those who need more immediate treatment. One of the early treatment algorithms was established, based on clinical research, by investigators at the University of Toronto. Those considered eligible for active surveillance under that algorithm have

  • a PSA of 10 ng/ml or less

  • a Gleason score of 6 or less

  • T1c to T2a prostate cancer.

For men with a life expectancy greater than 15 years, the cancer should be in only one or two cores and constitute less than half of those cores. Other institutions say that patients with T2b or T2c cancer can pursue active surveillance.

The Toronto researchers recommend suspending active surveillance if either of the following happens:

  • The patient's PSA doubles in less than three years (from 4 ng/ml to 8 ng/ml, for example).

  • The patient's Gleason score rises to 7 (4+3) or more after a repeat biopsy.

Some doctors suggest treatment if any component of the Gleason score is 4 (a 3+4, for example), if three or more biopsy cores are positive, or if significant changes are noted during a DRE.

Active surveillance has created a cauldron of controversy within medical circles. On one hand, cancer becomes much more difficult to treat once it pushes beyond the boundaries of the prostate; that makes this approach less than ideal for men with aggressive tumors. On the other hand, some prostate cancers may take 15 to 20 years or more to grow and cause little harm. Unnecessary treatment becomes a greater risk to the well-being of men with slow-growing tumors than the tumors themselves.

Origins of active surveillance

Epstein JL, Walsh PC, Carmichael M, Brendler CB. Pathological and Clinical Findings to Predict Tumor Extent of Nonpalpable (Stage T1c) Prostate Cancer. Journal of the American Medical Association 1994;271;368–74. PMID:7506797.

Surgery

Men have better options for surgical treatment 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 2002 landmark study by Scandinavian researchers provided the first clear evidence that surgical removal of the prostate gland lessened the chance of dying of prostate cancer. Results showed that after six years, 4.6% of men who'd had a prostatectomy had died from the disease, compared with 8.9% of those who'd relied on active surveillance (see "Survival benefit of surgery"). In 2008, the same group reported a difference of 5.4% in prostate cancer survival between the two groups. However, there was no difference in overall survival between the two groups, and there was no further increase in benefit 10 or more years after surgery. 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 surgery are men whose disease is confined to the gland itself (stages T1 and T2), 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 (see "Experience matters" and "Ask a doctor").

Experience matters

Begg CB, Riedel ER, Bach PB, et al. Variations in Morbidity After Radical Prostatectomy. New England Journal of Medicine 2002;346:1138–44. PMID: 11948274.

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.

Ask a doctor

How can I find and choose the best surgeon?

Start by obtaining a list of experienced prostate surgeons from an oncologist who specializes in prostate cancer or from an experienced primary care doctor in your area who is familiar with prostate care. Meet with one or two of them. Ask about their training in prostate surgery (did they complete a fellowship or other advanced training?), their past and current surgical volume, and their results with respect to cancer control and long-term outcomes relating to impotence and incontinence. Ask to speak with patients that they have operated on.

You should feel that the surgeon and his or her team will properly care for you after the surgery, too. Ask about postoperative follow-up. What access will you have to the surgeon or other members of the team? Does he or she give out an e-mail address, cell phone number, or pager number?

In short, you should feel comfortable speaking with the surgeon and asking questions — and you should feel comfortable with the answers.

— Andrew A. Wagner, M.D.
Director of Minimally Invasive Urologic Surgery, Beth Israel Deaconess Medical Center

Undergoing radical prostatectomy. During this procedure, which usually requires general anesthesia, the surgeon removes the patient's prostate and seminal vesicles (saclike glands that release fluid that 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 prostate and lymph nodes through several keyhole incisions in the abdomen. An increasingly common variation of the laparoscopic method is robot-assisted prostatectomy. With this technique, the surgeon sits at a console and remotely controls instruments placed through several keyhole incisions. Another option is the perineal technique, in which the surgeon works through an incision in the perineum, the area between the scrotum and the anus.

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 (see Figure 11), which is technically less difficult to perform (once the surgeon has learned how to use the device) than the standard laparoscopic technique. Early studies comparing robotic and standard laparoscopic techniques show no differences in controlling cancer when each is performed by an accomplished surgeon.

Figure 11: Operating robotically

Operating Robotically

To perform a robot-assisted laparoscopic prostatectomy, the surgeon sits at a console several feet away from the operating table and manipulates robotic arms fitted with tiny cameras and surgical instruments to locate and remove the diseased prostate gland. The console contains two full-color computer screens that provide a magnified, three-dimensional view of the prostate and surrounding tissues. The surgeon guides the robotic arms by manipulating the controls while watching the screens.

Some surgeons suggest that laparoscopic surgery (with or without robotic assistance) can speed recovery, and a 2009 study in The Journal of the American Medical Association that included 8,837 Medicare patients showed that it shortens the hospital stay by about one day. But the study also concluded that complication rates may differ between open and laparoscopic surgery (see "Surgical results"). Men who underwent laparoscopic surgery were less likely to need a blood transfusion or develop respiratory complications, but they were more likely to develop urinary incontinence and erectile dysfunction than those who had open surgery.

A Massachusetts study of 206 men who underwent open surgery or non-robotic laparoscopic surgery came to a slightly different conclusion. Writing in The Journal of Urology, the researchers found a modest increased risk of major and minor complications — the development of fluid-filled cysts, a narrowed passageway where the urethra is reconnected to the bladder, and blood in the urine — in the men who had laparoscopic surgery. But there were no differences in erectile function, continence, activity levels, or cancer control between the groups one year after surgery. Variations in patient populations may account for the studies' differing conclusions.

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 pelvic lymph nodes.

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 a so-called nerve-sparing operation was developed. During this surgery, doctors attempt to spare the two bundles of nerves that lie on either side of the prostate gland and control erections (see Figure 12). This type of operation may also reduce the likelihood of other serious side effects, such as urinary incontinence and significant blood loss.

Figure 12: The prostate and its nerves

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, the procedure is a delicate task that should be performed by a skilled urologic surgeon. The nerves that are responsible for erections are often damaged during the operation, so impotence is a common complication. A variation on this procedure, the nerve-sparing prostatectomy, attempts to preserve potency by removing the prostate without disrupting the nerves.

Not surprisingly, almost everyone undergoing prostatectomy wants the nerve-sparing procedure, and it's available across the country. However, success is not guaranteed. If the tumor is too close to a nerve bundle, the nerves can't be saved — and saving one nerve bundle is not as likely to preserve erectile function as saving both of them. Even if the procedure is successful, it can take a year 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 sufficiently skilled at the operation.

Recovery of sexual function also depends on the patient's age and the location of the tumor. Medication may be prescribed to help this process (see "Erectile dysfunction and urinary incontinence").

Patient interview: When active surveillance may be less than ideal

For many men with early-stage prostate cancer, pursuing active surveillance makes sense. They have, say, a total Gleason score of 6 and cancer in a relatively small percentage of just one or two biopsy cores. So, if the cancer itself isn't aggressive, why undergo aggressive treatment and risk complications like impotence and incontinence? Instead, the thinking goes, track the cancer over time and begin treatment when it becomes more active.

But not every patient's situation can be handled in such a straightforward manner, and Kirby Parsons' story illustrates that point. About seven years ago, Parsons* began to have symptoms of benign prostatic hyperplasia (BPH). The urge to urinate could wake him from a sound sleep, but in the bathroom, he had trouble starting to urinate. Afterward, he felt as though his bladder never completely emptied.

Two-and-a-half years ago, Parsons, a doctor himself, had his prostate-specific antigen (PSA) level checked. It was 13.9 ng/ml, up from just 2.8 ng/ml six months earlier. The rise was too rapid to suspect that BPH alone was the cause. The hope was that the high PSA was due to a recent case of prostatitis. When medication to treat the prostatitis and ease the symptoms of BPH didn't lower his PSA by as much as expected (see "BPH drugs and PSA"), he reluctantly had a prostate biopsy. The results: 5% of two cores contained cancer, which was graded a Gleason 3+3; 18 other tissue samples were normal.

BPH drugs and PSA

One class of drugs for BPH, 5-alpha-reductase inhibitors, not only reduces the size of the prostate, but also lowers PSA levels by about 50%. Dutasteride (Avodart) and finasteride (Proscar) are 5-alpha-reductase inhibitors. Because a high PSA may indicate prostate cancer, most physicians suggest getting a baseline PSA value before beginning treatment with a 5-alpha-reductase inhibitor, and then having another test six months later to see how much the PSA level was affected. A PSA that doesn't drop by about half may suggest prostate cancer and should prompt a discussion about having a prostate biopsy. A PSA that does drop by half would become the new baseline for future prostate cancer screening.

Short of not having prostate cancer, such findings constitute relatively good news; Parsons could pursue active surveillance. Instead, despite the risks, he opted for a radical prostatectomy, which took place in December 2009. Why not try active surveillance? Did the prostatectomy relieve his urinary symptoms? Does he have any regrets about his treatment decision? In August 2010, Parsons shared his thoughts on these questions with the editors of the 2011 Annual Report on Prostate Diseases.

*Editor's note: To protect his privacy, the patient's name and some biographical details have been changed. All medical details are as reported. In keeping with editorial policy, the patient's physicians are not named.

What symptoms of BPH did you have and how long had you been experiencing them?

Because the symptoms came on gradually, it's hard to remember when they became really bothersome, but I probably started having symptoms six or seven years ago. I was getting up two or three times a night to urinate, had a feeling of not fully emptying my bladder, and had difficulty starting a stream of urine, which was more of a problem when I was traveling and was in an airport bathroom or in a sports stadium. I had also had a couple of episodes of prostatitis; one of them actually occurred after a long trip. It was a real rip-roaring case of bacterial prostatitis, and it was remarkably uncomfortable.

How long ago did that happen?

That was about two-and-a-half years ago.

What were your symptoms?

I had very diminished urine flow, episodes of urination every half-hour to an hour, dribbling, groin pain, lower abdominal pain, and a fever.

What was your PSA at that point?

We didn't do a PSA then because it would have been overly high due to the infection. But shortly after the prostatitis, I did have my PSA measured and it was 13.9 ng/ml. My PSA about six months before that was 2.8. I was almost 57 years old at the time.

Is there any history of prostate trouble in your family?

My father had both BPH and prostate cancer. He didn't die from prostate cancer, but it was diagnosed late in life, following a PSA test. That was before PSA was being routinely measured, and his was about 20 ng/ml. Because of his age, he was treated with hormone therapy and radiation. He died of Alzheimer's disease at age 80; an autopsy found no evidence of any residual prostate cancer.

Following the episode of acute prostatitis, did your urinary symptoms dictate your day?

I've always been a coffee drinker, and I like drinking coffee in the morning. I think that's why my symptoms were generally worse in the morning. I would have to urinate every 45 minutes to an hour, and I never really felt like my bladder completely emptied. Luckily, I work in a private office. There's a bathroom right across the corridor, and I can pop in and out of there quickly.

But my symptoms were a big issue when I was traveling. At one point, I took a trip overseas. I was touring with a group, and despite having taken Flomax [tamsulosin] twice a day for some time, and taking Avodart [dutasteride], too, going to the bathroom was always on my mind. Whenever we arrived somewhere, I was generally the first one into the bathroom and the last one out. It was more than a simple annoyance. It was something I really worried about.

When did you start taking medication for BPH?

I started taking Flomax in 2004 or 2005 because of the nighttime awakening. It didn't really work, so eventually the dose was increased. After the episode of prostatitis, my urologist recommended taking Avodart, too, so I started taking that in December 2007. It had some negative side effects. It affected my libido, and semen volume seemed to go down. And I didn't particularly like the way I felt. Also, I was always worried that I was going to run out of medication. When I traveled, I was certain to pack Flomax in my suitcase. In my carry-on bag, I packed twice what I'd need because I was really afraid of running out and going into acute urinary retention.

Did you ever experience acute urinary retention?

No, but when I had the episode of acute prostatitis, I think I was almost at that point. I did not have a post-void residual measured at that time, but I had been experiencing chronic urinary retention. [See "A urinary emergency."]

A urinary emergency

A man with acute urinary retention can't urinate at all. A medical emergency that can lead to kidney failure, acute urinary retention requires the insertion of a catheter to drain urine from the bladder. This condition is different from being unable to completely empty the bladder. (The leftover urine is called the post-void residual, or PVR.) Doctors can estimate the PVR volume using ultrasound. A PVR of 100 ml or greater is considered chronic urinary retention.

What was your understanding of what should happen to your PSA when you started taking Avodart?

I knew it should fall by about 50%, but I was a little unclear about where the 50% mark was, given that my PSA rose so high with the episode of prostatitis. Should it be 50% down from 13.9 or from 2.8 ng/ml?

I actually put off having my PSA remeasured because I was concerned about what the results would be. With a family history of prostate cancer, I suppose I expected to be diagnosed with the disease at some point. So, because I wasn't eager to have a biopsy, I wasn't eager to have my PSA remeasured.

So how did your urologist convince you to have a biopsy?

Well, I was having symptoms from BPH that were really getting very uncomfortable. I did have my post-void residual volume checked. I don't remember the number, but it was probably about 125 ml, just above the amount that defines chronic urinary retention. I was already on the maximum dose of Flomax, and I had been on Avodart for about a year. When the PSA was measured at that point at 2.7 ng/ml, we felt it really hadn't fallen adequately. Regardless of where it started, if the drugs had cut my PSA in half, that would mean my true PSA would be 5.4 ng/ml. That's a high PSA for a man in his late 50s. Given that PSA level, my family history, and my symptoms, I knew I needed to have a biopsy.

What was that experience like?

I remember hearing about prostate biopsies in the days before anesthesia was used, so I had been living in fear of the experience. But with some local anesthesia and a mild sedative beforehand, it was not nearly as bad as I had feared. It was quick, and it was not particularly painful. I wouldn't describe it as comfortable — a transrectal probe is not comfortable — but the biopsy itself was not terribly uncomfortable. Actually taking the biopsy samples probably lasted no more than three minutes. [For a description of what to expect during a transrectal ultrasound and a prostate biopsy, see "Ultrasound" and "Biopsy."]

What were the findings of the biopsy?

I had a saturation biopsy, so 20 cores were taken. The pathology was abnormal in two of the 20 cores, so 18 cores showed no evidence of cancer. The cancer had a Gleason score of 3+3 in less than 5% of the two cores.

Interestingly, based on the ultrasound, the doctor estimated the volume of my prostate to be 61 ml, which is relatively large. An earlier workup showed my prostate to be 60 ml. After taking Avodart, which is supposed to shrink the prostate, for a year, my prostate went from 60 to 61 ml, even though I didn't miss a dose.

One thing I'm very grateful for is that my urologist did a 20-core biopsy because, given that cancer was only present in two samples, the likelihood that an eight- or 10-core biopsy would have shown cancer is relatively low. This really demonstrates that biopsy techniques are far from perfect. A man can have cancer, and the biopsy can miss it.

Given the nature of your cancer, you could have opted for active surveillance. Why did you decide to have a radical prostatectomy?

The way I viewed it, and the way my urologist viewed it, was that I was uncomfortably symptomatic with BPH and lower urinary tract symptoms. I was on the maximum doses of medications that were supposed to control the symptoms, but they weren't working. So I needed a procedure to reduce the size of my prostate, such as a TURP [transurethral reduction of the prostate], TUEVP [transurethral electrovaporization of the prostate], or laser surgery. [For a description of these and other surgical procedures for BPH, see "Surgery," "Laser procedures," and "Other treatments for BPH."] But would having one of those procedures make sense for someone with prostate cancer? I didn't think so.

I could have tried radiation therapy, but I felt that radiation made no sense for me. It would probably make my prostate more inflamed, increasing the odds that I would experience acute urinary retention. Given the size of my prostate, I would've had to take hormones to shrink it prior to radiation, and I didn't want to take hormones. I was also an inappropriate candidate for brachytherapy because my prostate was larger than 50 grams.

That left me with two choices: have no treatment and continue to put up with the urinary symptoms, or treat the cancer, and thus the BPH and the urinary symptoms, with a radical prostatectomy. I decided that the radical prostatectomy would be the best thing for me.

Did you look into the various types of radical prostatectomy — laparoscopic, robotic, and open?

I did. I also decided that I wasn't going to look outside of Boston for a surgeon, even though people said that there were great programs in New York and Baltimore. The idea of traveling somewhere to have surgery just didn't appeal to me. I wanted to go comfortably to and from the hospital and my surgeon's office; the difficulties and hassle of traveling to another city would far outweigh any minimal difference in surgical expertise. So I visited the best and the busiest robotic and open surgeons in Boston.

I decided to have the open surgery because of the expertise and experience of the open surgeon. And based on what I read at that time, robotic surgery didn't really seem to have a proven benefit. There have been studies, but I don't think they adequately took experience into account. [See "Undergoing radical prostatectomy" and "Surgical results."]

The robotic surgeon told me that his first 200 cases were not done as well as his last 200 cases. When I mentioned this to the open surgeon, he said, "Well, my first 5,000 cases weren't as good as my last 5,000 cases. The learning curve never ends. It may flatten, but it never really ends." I thought that was an interesting point.

I decided that spending fewer days in the hospital and getting back to work a few days sooner — the benefits of robotic surgery — weren't important enough for me to risk complications or a less effective outcome in terms of cancer control.

Surgical results

Dahl DM, Barry MJ, McGovern FJ, et al. A Prospective Study of Symptom Distress and Return to Baseline Function After Open Versus Laparoscopic Radical Prostatectomy. Journal of Urology 2009;182:956–65. PMID: 19616252.

Hu JC, Gu X, Lipsitz SR, et al. Comparative Effectiveness of Minimally Invasive vs. Open Radical Prostatectomy. Journal of the American Medical Association 2009;302:1557–64. PMID: 19826025.

Had you not had urinary problems, what treatment would you have had?

Had I had no urinary symptoms at all, I would have been leaning toward active surveillance.

Even with your family history?

That was the one piece that made me uncomfortable with active surveillance.

What would you have done if the biopsy came back negative for cancer? How would you have treated your BPH?

I'm not sure. I probably would have opted for no additional treatment, given all the potential side effects. With nothing pushing me to make a decision, I probably would have waited to do something until I developed acute urinary retention. I might have tried other alpha blockers, Uroxatral [alfuzosin] or Cardura [doxazosin], to see if they would work any better for me than Flomax. And I might have tried finasteride [Proscar] in place of Avodart, given my non-response to it in terms of prostate volume. But I would likely be suffering more today if I hadn't had the radical prostatectomy.

Speaking of the surgery, what was the postoperative period and recovery like?

I had a hard time the first two days after surgery because the painkillers caused side effects, such as nausea and stomach upset. After my medication was changed, I was much more comfortable. I was in the hospital for three-and-a-half days, but I probably could have left sooner had I changed painkillers earlier. After I went home, I didn't really need any pain medication. The one medication that I did use was for sleep — I found that I was able to sleep comfortably despite having the catheter in place.

Within about five days, I started checking my work e-mails, logging on to my office computer, taking a few phone calls, and reading mail. I didn't feel comfortable going out while I still had the catheter, so I didn't really leave the house until I went to the hospital to have it removed, which was about nine or 10 days after surgery. I actually went back to work part-time after about three weeks, even though I had planned to be out for up to six weeks.

Presumably, you've stopped taking Flomax and Avodart. How is your urinary function now?

I stopped taking Flomax and Avodart the day of the surgery. And from the day the catheter was removed, I haven't had any significant urinary symptoms — no diminished flow or feelings of obstruction. In fact, the change in how quickly and completely I can empty my bladder has been dramatic.

How have you felt since undergoing surgery, and are you pleased with the outcome?

My first goal was to be cancer-free, but not far behind that was my desire to take care of the BPH and have the urinary symptoms under control. The downsides to surgery for me — urinary incontinence, leakage, and sexual function — were much less important. Clearly, the cancer has been taken care of. My PSA is undetectable, and I'm not at risk for a recurrence. I have no problems with urinary flow or incontinence. I was on another trip not that long ago and, as opposed to the trips where I was the first one in the bathroom and the last one out, I'm now the first one out.

Leakage has not been a significant issue. Initially, there was a little bit, so I wore pads. Now, if I'm going to be out of reach of a bathroom for long periods of time, I'll wear a pad just in case, but more than 90% of the time, I haven't needed it. And I don't wear a pad at night.

Erectile dysfunction is still an issue, but I had surgery only eight months ago, so the jury is still out on that. Doctors say it can take 18 months to two years to recover erectile function. As of now, that's the only issue I'm still dealing with.

I will say that since I stopped taking Flomax, I haven't had the lightheadedness and dizziness that I used to get. And having stopped Avodart, my libido is a little better.

What advice do you give your male patients who are in a similar situation?

I have quite openly shared my own experience with my patients. Before my treatment, I kept things very private, but afterward, I've almost felt obligated to discuss my experience. I tell people with prostate cancer that, unlike with other types of cancer, there's no one single approach to treatment. Every man's story is unique. You can't say, "Well, this man had brachytherapy, so that's what I'm going to do," or "My friend is doing active surveillance, so that's what I'm going to do." Treatment really has to be individualized, much more so than with other malignancies. I've told people that they need to recognize the uniqueness of their own situation.

I also recommend that people gather as much information as they can about various therapies and be thoughtful about their treatment choice. I know that people can become paralyzed by information because when you do research on the Internet or talk to people, there's always one more thing to consider. But my advice is to get as much information as you can, focus on the things that are most important to you and prioritize them, and then think about how the various therapies fit with your priorities.

As a physician, you probably knew a lot about prostate cancer before you even started to study your own situation. Could you have become paralyzed by all of that information?

Yes, I think so. As a physician, there's an expectation of understanding things to an even greater level. You look through all the levels of nuance and think through experimental data. It could really derail one's ability to focus on making a decision. Many people gave me information or suggested talking to yet another doctor at a hospital across the country. After a while, all of that information could have been paralyzing. That's why you have to focus on your priorities, what makes you comfortable, and the uniqueness of your own situation.

Radiation therapy

This treatment, which uses radiation to destroy cancerous cells, is a reasonable alternative to surgery. 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 (an approach called brachytherapy). To improve survival, radiation therapy is sometimes used in combination with a form of hormone therapy known as adjuvant hormone 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 years later, when it can no longer be treated with radiation. 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. (See "What's the right age for radiation therapy?") And in theory, cancer cells may be left behind or missed during surgery — cells that might have been killed with radiation. No large, well-designed trials have compared surgery to radiation, although one, the ProtecT study, is under way.

What's the right age for radiation therapy?

Any man with prostate cancer can elect to have radiation therapy. But prostate cancer cells can sometimes survive a full course of radiation, meaning that the disease may recur years later, when it can no longer be treated with radiation. (There is a limit to how much radiation one can have.) This is the main reason why urologists tend to recommend surgery for men with early-stage cancer who are age 60 or younger, and to recommend radiation therapy for men over age 70. Between these ages, the choice of treatment will hinge upon several factors, such as your general health, life expectancy, urinary and erectile function, lifestyle, and preferences, as well as the extent of your cancer. However, radiation oncologists often disagree with these age breakdowns, and improved techniques are leading many to challenge once widely held beliefs about age and radiation therapy.

External beam radiation is sometimes used after surgery if tissue that has been removed reveals the cancer has spread beyond the prostate capsule (stage T3). Or it may be used some months after surgery if a PSA test indicates the presence of residual cancer.

External beam radiation. Most patients who undergo radiation therapy receive external beam therapy (see Figure 13), in which rays of high-energy radiation are aimed directly at the prostate tumor (and sometimes at nearby lymph nodes). External beam radiation therapy effectively destroys cancer cells, but it can also damage adjoining healthy tissue. To limit the collateral damage, a specialist determines the exact location of the tumor using a CT scanner. This technology relays images 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 tissue nearby.

The therapist places the patient on the table in exactly the right position, checks the computer settings, and finally activates the device that delivers the radiation.

Figure 13: External beam radiation therapy

External beam radiation therapy

During external beam radiation for prostate cancer, a patient will typically wear a gown or sweat pants that can easily be removed so that the area to be treated can be aligned with a ray of light that matches the path of the radiation. The radiation beam itself is not visible. Marks on the skin or metallic gold implants (called gold fiducials) in the prostate help pinpoint the gland's location. The patient may also lie in a custom-made body "cast" to immobilize the pelvis.

Several types of external beam radiation therapy are used:

  • Three-dimensional conformal radiation therapy (3D-CRT) is the standard form of outpatient radiation therapy. As noted above, it involves taking three-dimensional pictures of the prostate and surrounding structures before treatment to pinpoint their locations. Using computer software, radiation oncologists and physicists determine the angles at which the beams of radiation should enter the tissue. In this way, the radiation field conforms to the shape of the treatment area and helps keep radiation away from the bladder and rectum.

  • Intensity-modulated radiation therapy (IMRT) is a form of 3D-CRT that allows doctors to change the intensity of the radiation within each of the radiation beams — increasing radiation to the prostate while reducing radiation to normal tissues. Because treatment conforms so tightly to the prostate, its exact location must be determined at the start of each treatment.

  • Proton beam therapy exhibits the same precision as IMRT, but it uses protons instead of photons, which are used in conventional radiation, to treat cancer cells. Theoretically, less radiation leaves the prostate than with photons. 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.

  • CyberKnife uses image guidance and computer-controlled robotics to deliver multiple beams of radiation to the tumor from almost any direction. The system tracks the tumor's position, detects prostate movement, and automatically adjusts the delivery of radiation, if necessary, to account for any change.

  • TomoTherapy incorporates software for treatment planning with a CT scanner and the radiation delivery device into a single machine. With its circular shape, the machine can deliver radiation therapy continuously from any angle around the patient. Individual beams can also be divided into smaller "beamlets" to conform to the tumor's contours.

Treatment is painless. Depending on how the radiation is delivered, treatment sessions can last from about 15 minutes (as with 3D-CRT, IMRT, and proton beam therapy) to an hour or longer (as with CyberKnife). Because the dose of radiation must be spread out over time, treatments are generally repeated five times a week for about eight weeks. (CyberKnife and TomoTherapy take less time.) This time commitment can be difficult if you don't live or work near the treatment facility.

At this time, no convincing studies exist to suggest that one form of radiation is superior to the others in the treatment of prostate cancer. However, the different types do have advantages and disadvantages that you'll want to consider carefully before making a treatment decision. To compare them, see Table 6.

Table 6: Comparison of forms of radiation therapy

Treatment

Ideal candidates

Treatment time and recovery

Possible side effects

Advantages

Disadvantages

Three-dimensional conformal radiation therapy (3D-CRT)

Older patients or those with multiple medical conditions; patients whose cancer has spread outside the prostate capsule; men who have had a transurethral resection of the prostate (TURP).

35–45 treatments (five times a week for seven to nine weeks); each treatment takes about 15 minutes.

Bowel problems (diarrhea, blood in stool, rectal leakage, rectal pain), frequent urination, blood in the urine, urinary incontinence (increases over time), impotence (develops slowly), fatigue.

Widely available.

Now the standard in outpatient radiation therapy.

Length of treatment makes it inconvenient, especially for men living far away from a treatment facility or those who travel frequently.

Intensity-modulated radiation therapy (IMRT)

35–40 treatments (five times a week for seven to eight weeks); each treatment takes about 15–20 minutes.

In theory, allows more accurate targeting of the tumor so that there's less damage to surrounding healthy tissue. The intensity of each of the beams can be adjusted.

Length of treatment makes it inconvenient, especially for men living far away from a treatment facility or those who travel frequently.

Not offered at every treatment facility.

In rare cases, the radiation may miss part of the tumor if the beam is too narrowly focused.

Proton beam therapy

35–45 treatments (five times a week for seven to nine weeks); each treatment takes about 15 minutes.

May be able to deliver more radiation to the prostate and less to surrounding tissues, causing less damage to nearby structures; protons release their energy after traveling a certain distance, limiting damage to the tissue they pass through.

Available at only five sites in the United States.

May not be covered by insurance.

More research is needed to determine whether it reduces side effects.

CyberKnife

Older patients or those with multiple medical conditions; patients whose cancer has spread outside the prostate capsule; men who have had a transurethral resection of the prostate (TURP).

Usually five outpatient treatments, each lasting 60 to 90 minutes. May require fewer treatments if combined with another form of radiation.

Bowel problems (diarrhea, blood in stool, rectal leakage, rectal pain), frequent urination, blood in the urine, urinary incontinence (increases over time), impotence (develops slowly), fatigue.

Corrects for small movements and changes in the prostate during the course of treatment.

Limited availability.

More research is needed to prove its effectiveness.

TomoTherapy

Number of treatments varies depending on tumor characteristics. Each treatment lasts about 25 minutes.

Integrates CT scanning at each visit to correct for changes in the prostate. Beams rotate 360 degrees around the patient for greater accuracy.

Device hasn't been commercially available for very long. It's not available in all areas.

Permanent seed implants (brachytherapy)

Men with early-stage cancer and prostate volume of less than 60 ml.

May be beneficial in men with inflammatory bowel disease or cancer close to the bowel.

Half-day to full-day outpatient procedure with anesthesia.

Impotence and urinary and bowel problems.

Pain and rectal irritation usually resolve in about a month.

Radiation is concentrated in the prostate, potentially sparing the urethra, bladder, rectum, and nerves.

Can be used with external beam radiation in high-risk patients.

Small risk that unlinked seeds will migrate or be passed in the urine. Rarely, seeds enter the bloodstream and travel to the lungs or other parts of the body.

Urinary symptoms may be worse initially than with external beam radiation.

High-dose-rate brachytherapy

Intermediate- and high-risk patients.

Usually three treatments over a few days; treatments last about 15 minutes.

Needles remain in place until after the final treatment.

Requires a hospital stay.

Limited availability.

Brachytherapy. Rather than delivering radiation from an external source, brachytherapy delivers radiation from a source placed inside the body. As a result, it's sometimes called internal radiation therapy or interstitial radiation therapy. The most common form of brachytherapy is permanent brachytherapy, or seed implantation. This involves placing 60 to 100 radioactive seeds or pellets (depending on the size of the prostate gland) in or near the prostate tumor (see Figure 14).

Figure 14: Permanent brachytherapy (seed implants)

Permanent brachytherapy (seed implants)

Most radiation oncologists use three-dimensional treatment planning and a template guide to precisely implant radioactive seeds and to ensure that radiation is evenly distributed throughout the prostate. Ultrasound, delivered through an ultrasound probe, or transducer, allows them to view the prostate throughout the procedure.

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 seeds, using a template and a needle to insert them through the perineum. Doctors leave the seeds, which are smaller than grains of rice, in place permanently. Over time, the seeds emit less and less radiation until they become inert, which takes three months to a year, depending on the type of seeds. The radiation does not affect other people.

Permanent brachytherapy is usually an outpatient procedure, and most men return home as soon as the anesthesia wears off. If you have permanent brachytherapy, you will need to abstain from sex for about two weeks and then use a condom for several weeks to protect your partner from radiation exposure. (Initially, the ejaculate may be bloody and low in volume.) There usually aren't any other restrictions.

There is a small risk that the seeds will be discharged during urination, so some doctors suggest straining the urine for a few days, though iodine seeds can be flushed down the toilet. In rare cases, when seeds are not linked together, a seed can enter the bloodstream and travel to the lungs or another part of the body. (Most seeds are linked.) The radiation emitted by a single seed is low, so it shouldn't pose any significant health problems.

Some men choose seed implants because they are more convenient than external beam radiation, requiring only a single treatment. As for side effects, data suggest that brachytherapy and external beam radiation are equally likely to lead to impotence or incontinence.

In comparisons of 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 (for up to five years) between men who had brachytherapy and those who had radical prostatectomies for localized prostate cancer. The men who received the seeds enjoyed better sexual function and fewer urinary symptoms than the ones who had a 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 probably is the better choice. The study found that seed implants are much less effective than had been thought, and it questioned their use in men with intermediate or late-stage tumors. (To read these studies on your own, see "Brachytherapy insights.")

Brachytherapy insights

Bacon CG, Giovannucci E, Testa M, Kawachi I. The Impact of Cancer Treatment on Quality of Life Outcomes for Patients with Localized Prostate Cancer. Journal of Urology 2001;166:1804–10. PMID: 11586228.

Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of Life Outcomes After Brachytherapy for Early Stage Prostate Cancer. Journal of Urology 2000;163:851–57. PMID: 10687991.

D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical Outcome After Radical Prostatectomy, External Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer. Journal of the American Medical Association 1998;280:969–74. PMID: 9749478.

In rare cases, a doctor may suggest a different type of brachytherapy called high-dose-rate brachytherapy. As with permanent brachytherapy, the radioactive material is inserted into the prostate. But given the high intensity of the material, it cannot be left in the body for long. After a set period of time, a remote-controlled machine pulls the material out. The process is then repeated several times in one day or over multiple days. Catheters remain in place until after the final treatment.

One reason most radiation oncologists don't use high-dose-rate brachytherapy is that it's difficult for patients to have the catheter in the perineum for a few days. And because it lacks the speed and convenience of permanent brachytherapy, many patients avoid it. However, in patients with intermediate- and high-risk tumors who plan to undergo external beam radiation, having high-dose-rate brachytherapy beforehand might kill tumor cells more effectively. It could also reduce the number of weeks of external beam radiation from eight to about five. But most radiation facilities do not offer high-dose-rate brachytherapy because other treatments are less complicated and usually just as effective.

Ask a doctor

Is proton beam radiation better at treating prostate cancer than IMRT?

Proton beam is a rather sophisticated form of external radiation that may have some advantages over more standard intensity-modulated radiation therapy (IMRT) in terms of accuracy. This may result in fewer side effects, but to be honest, the side effects are relatively low with IMRT radiation already. Although proton beam therapy has shown considerable benefits in treating tumors in other, more critical parts of the body, such as the brain and eyes, no one has yet demonstrated a clear benefit in the prostate using the current proton techniques. What is really needed is a randomized trial to determine whether these theoretical advantages truly exist or not. It is not, as one might have read on the Internet, a closed case. Indeed radiation treatment with brachytherapy (seeds) may be even more accurate than proton beam. A randomized trial comparing proton beam with IMRT is being developed at Massachusetts General Hospital and the University of Pennsylvania.

Proton beam therapy, like IMRT, is not risk-free. Some men experience urinary urgency or rectal bleeding, although these complications are usually temporary. Unfortunately, it is no more effective than other kinds of radiation in avoiding impotence. Approximately 30% to 50% of patients will ultimately suffer from this problem.

The future is likely to bring advances in proton beam technology that may open up a gap between it and IMRT, but the gap is likely to be small. As a society, we'll need to ask some hard questions about whether the small gains are worth the additional — and substantial — cost.

— Anthony L. Zietman, M.D.
Radiation Oncologist, Massachusetts General Hospital

Cryotherapy

Cryotherapy, also called cryosurgery and cryoablation, kills cancer cells by freezing them. It's not exactly a new procedure — physicians have used cryotherapy to destroy skin tumors and precancerous moles since the 1960s. But it wasn't until the 1990s, after significant improvements were made in imaging technology and the devices that control extreme temperatures, that researchers started testing cryotherapy on tumors inside the body. Before that, doctors had no way to monitor the treatment internally or see how much tissue had been frozen.

To treat prostate cancer, a physician guides several small needles into the patient's prostate gland through the perineum (see Figure 15) while the patient is under anesthesia. To accurately position the needles and tailor the treatment to the tumor's shape and location, the physician relies on real-time images of the prostate generated by an ultrasound probe inserted in the rectum. To help protect the urethra from freezing, the physician inserts a warming catheter. This also helps keep dead tissue from blocking urine flow later on. Similarly, the physician inserts warming needles into the tissue between the prostate and the rectal wall to prevent damage to the rectum.

Figure 15: Cryotherapy

Cryotherapy

During modern cryotherapy, a physician inserts several thin needles into the prostate. The needle tips are rapidly cooled to –40° C with argon gas, which freezes prostate tissue and destroys cancer cells. A rectal ultrasound probe generates real-time images that allow the physician to monitor cycles of freezing and thawing. Warming needles (not shown) inserted between the prostate and rectal wall prevent damage to the rectum.

During the procedure, the cryotherapy unit super-cools the needle tips in the prostate with argon gas. (Early prostate cryotherapy used liquid nitrogen for freezing, which necessitated the use of thicker probes. Today's thinner needles and the use of a gas instead of a liquid allow for greater treatment precision.) For cryotherapy to be as effective as possible, tissue must be rapidly frozen — temperatures plunge to about –40° C — and then slowly thawed at least twice. As sharp, jagged ice crystals form inside the cells, they tear the cells apart. Cells may also burst when they swell and shrink during the repeated cycles of freezing and thawing. Ice forms inside the small vessels feeding the tumor, too, choking off its blood supply. To determine when tissue has been sufficiently frozen, the physician checks ultrasound images of the prostate and monitors the temperature in and around the gland.

Results have varied depending on the type of equipment used and the definition of biochemical progression, making it difficult to draw direct comparisons between groups of patients (see "A selection of articles on cryotherapy"). However, even among patients at high risk of disease progression, most of those who undergo cryotherapy with argon and ultra-thin needles don't experience biochemical recurrence during the next several years. As a result, cryotherapy appears to be an effective treatment for prostate cancer.

A selection of articles on cryotherapy

Bahn DK, Lee F, Badalament R, et al. Targeted Cryoablation of the Prostate: 7-Year Outcomes in the Primary Treatment of Prostate Cancer. Urology 2002;60 (Suppl 2A):3–11. PMID: 12206842.

Donnelly BJ, Saliken JC, Ernst DS, et al. Prospective Trial of Cryosurgical Ablation of the Prostate: Five-Year Results. Urology 2002;60:645–49. PMID: 12385926.

Most complications from cryotherapy, such as incontinence, urinary obstruction, and the development of a fistula (a hole in the rectum), have decreased dramatically thanks to modern technology and the evolution of techniques to keep the urethra and rectum warm. (A rectal fistula is now quite rare.) But nearly all patients who are potent before treatment are impotent afterward because there's no way to avoid freezing some nerves.

Older patients and those with multiple medical conditions that might be aggravated by surgery or radiation find cryotherapy an attractive option. Others who might want to consider cryotherapy include patients who

  • have cancer that may have spread locally, increasing the likelihood of positive margins with a radical prostatectomy (cryotherapy can freeze cancers that have escaped from the prostate)

  • have a moderate to high risk of recurrence even after surgery or radiation therapy (unlike other procedures, cryotherapy can be repeated)

  • opt for hormone therapy and later find out that their PSA is rising again

  • do not want radical surgery or other procedures.

Although approved by the FDA and covered by Medicare, cryotherapy for localized prostate cancer isn't widely offered, so finding experienced physicians in your area may be challenging. Be sure to ask practitioners about their technique and how many procedures they've done.

High-intensity focused ultrasound (HIFU)

When physicians use ultrasound as a diagnostic tool, the low-intensity sound waves deposit small amounts of energy as they travel through tissues. According to how much energy the tissues absorb (and how much they reflect), they look white, black, or gray in the resulting pictures. By increasing the intensity of the sound waves and focusing them on a single point, HIFU sends a large amount of energy into the tissue, in this case, the prostate (see Figure 16). The energy creates heat — temperatures can rise to 60° C or higher — that irreversibly damages cells in seconds. The sound waves also create vibration, which disperses the energy and enhances tissue destruction.

Figure 16: High-intensity focused ultrasound (HIFU)

High-intensity focused ultrasound (HIFU)

High-intensity focused ultrasound (HIFU) uses sound waves produced by a rectal probe to remove cancer. Pulses of energy destroy tissue at the point where all of the sound waves converge. Because the urethra runs through the treatment area, urinary infections, bladder obstruction, and incontinence are relatively common side effects.

HIFU destroys only a small volume of tissue with each pulse of energy. After treating one spot, the physician focuses the sound waves on the next point, making sure that the new treatment area overlaps a bit with the previous one. This process continues until the cancerous sections have been destroyed. Because tissue destruction occurs only at the point where the sound waves intersect, skin and other tissues are unharmed. Even so, HIFU devices monitor the temperature of the rectal wall, which is sensitive to temperature changes, and keep it cool during treatment.

Monitoring temperature in precise spots in the prostate with ultrasound is not yet possible, so physicians turn to magnetic resonance imaging (MRI) for this task. They also use MRI to monitor treatment, ensure tissue destruction, and avoid overheating surrounding structures. In addition, ultrasound images don't always accurately define areas that have been treated, so MRI has become the gold standard for evaluating the success of the procedure.

Proponents of HIFU tout the fact that it is even less invasive than cryotherapy. Physicians still use the rectal ultrasound probe, but they don't need to insert needles through the perineum and into the prostate. Like cryotherapy, HIFU can also be repeated if necessary.

Several scientific papers have concluded that HIFU appears effective for the treatment of prostate cancer (see "A selection of articles on HIFU"). For example, Japanese researchers reported in 2006 that 87% of 63 HIFU patients enrolled in a clinical trial had negative biopsies six months after the procedure. After a median period of 22 months, 75% were biochemically disease-free. And a French study of 227 patients noted that 86% of them had negative prostate biopsy specimens three months after HIFU. Although patients were followed only for an average of 27 months, researchers projected that 66% of them would be free of biochemical or pathologic recurrence after five years.

A selection of articles on HIFU

Blana A, Murat FJ, Walter B, et al. First Analysis of the Long-Term Results with Transrectal HIFU in Patients with Localised Prostate Cancer. European Urology 2008;53:1194–201. PMID: 17997026.

Dubinsky TJ, Cuevas C, Dighe MK, et al. High-Intensity Focused Ultrasound: Current Potential and Oncologic Applications. AJR 2008;190:191–199. PMID: 18094311.

Murat FJ, Poissonnier L, Pasticier G, Gelet A. High-Intensity Focused Ultrasound (HIFU) for Prostate Cancer. Cancer Control 2007;14:244–49. PMID: 17615530.

Poissonnier L, Chapelon JY, Rouvière O, et al. Control of Prostate Cancer by Transrectal HIFU in 227 Patients. European Urology 2007;51:381–87. PMID: 16857310.

Uchida T, Ohkusa H, Nagata Y, et al. Treatment of Localized Prostate Cancer Using High-Intensity Focused Ultrasound. BJU International 2006;97:56–61. PMID: 16336329.

Many of the patients participating in these studies reported urinary problems in the first few months after HIFU treatment. Some had difficulty urinating that was caused by swelling or by bits of tissue obstructing urine flow. Others suffered from incontinence, developed infections, or experienced changes in urinary frequency or urgency. In most cases, these side effects were only temporary. Reported impotence rates ranged from 20% to nearly 50%, though these numbers should be taken with a grain of salt because validated questionnaires of erectile dysfunction were not used consistently.

HIFU has not been approved by the FDA, so men in the United States seeking the treatment have traveled to Mexico or Canada for the procedure. In anecdotal reports, men have claimed that they are doing well, but others have said that their cancer was never eradicated and that they have had serious complications, such as incontinence. Until studies show the safety and effectiveness of HIFU over longer periods of time, men should consider undergoing it only as part of a clinical trial and only if they are older and have a limited life expectancy or if they cannot tolerate surgery or radiation therapy.

Physician interview: Targeted focal therapy for early-stage prostate cancer

Minimally invasive technique may effectively control cancer without compromising quality of life

When it comes to treating early-stage prostate cancer, options abound. At one end of the spectrum, patients can choose between doing nothing and active surveillance (postponing treatment of the cancer until it shows signs of progression with regularly scheduled follow-up tests). However, many physicians, including renowned urology researcher E. David Crawford, M.D., aren't comfortable suggesting these strategies to patients, especially those men who are likely to live more than 15 years. Crawford provocatively likens active surveillance to Russian roulette because by the time patients undergo treatment, the cancer may have advanced to the point where it can no longer be eradicated.

But treatments at the other end of the spectrum, including radical prostatectomy and radiation therapy, aren't ideal either. With these options, a man with a tiny tumor in just one part of his prostate risks urinary incontinence, impotence, and other complications that could dramatically affect his quality of life and, as recent studies suggest, does little to prolong his life. This, says Crawford, is the equivalent of treating cancer with an ax, but when told that they have cancer, most patients want it taken out right away.

Targeted focal therapy,* which uses minimally invasive techniques, could be a viable, middle-of-the-road solution. Treatment could focus specifically on the tumor, rather than the entire prostate. In theory, this would prevent the cancer from growing out of control while minimizing life-altering complications.

As chairman of the Southwest Oncology Group (SWOG) Genitourinary Committee for 28 years and senior associate director of the Comprehensive Cancer Center at the University of Colorado Health Sciences Center in Denver, Crawford has done many clinical trials, including studies that test targeted focal therapies. (A network of medical centers, universities, oncologists, scientists, statisticians, and administrators, SWOG develops and runs clinical trials.) Crawford, who is also a professor of surgery, urology, and radiation oncology, spoke with the editors of the 2011 Annual Report on Prostate Diseases about his research and the potential of targeted therapy for prostate cancer treatment in appropriately selected patients.

*Editor's note: The terms targeted focal therapy, targeted therapy, and focal therapy are used interchangeably in this article.

What is targeted therapy?

Instead of removing or ablating the whole prostate, targeted therapy, also called focal therapy, treats the part of the prostate where the cancer is located. You can compare focal therapy to a lumpectomy done for breast cancer; instead of mastectomy, which involves the removal of the entire breast, a lumpectomy means that only the cancerous mass is removed, sparing the rest of the breast. A radical prostatectomy is like a mastectomy because the entire prostate is removed.

We are very good at diagnosing prostate cancers, yet we're not good at knowing which ones to treat and which ones to leave alone. Prostate cancer is a slow-growing disease, so most men die with the disease rather than from it. But most men are not comfortable knowing they have cancer in their body and leaving it there. They want it out. If you look at the rate of active surveillance between 1990 and 2006, you'll see that it actually decreased. [See "Trends in prostate cancer treatment."] So, in spite of the fact that we are catching a lot of cancer earlier on, cancers that we might want to watch rather than treat, the number of men pursuing active surveillance is dropping. Most men don't want to sit on a cancer and most doctors don't want to sit on it either, so active surveillance often doesn't enter the discussion.

Trends in prostate cancer treatment

Cooperberg MR, Broering JM, Kantoff PW, Carroll PR. Contemporary Trends in Low-Risk Prostate Cancer: Risk Assessment and Treatment. Journal of Urology 2007;178:S14-19. PMID: 17644125.

Right now, the best way to detect prostate cancer is with the PSA test, but there's another test that's being investigated, called PCA3. It seems to complement the PSA. PCA3 is a noncoding messenger RNA that is pretty specific for prostate cancer. We've done a large study of almost 2,000 men, and found that PCA3 screening complements PSA — it enhances the specificity of PSA. [See "Getting specific."] If a person has cancer, PCA3 also reflects the volume of cancer. In the future, PCA3 might help us better screen for prostate cancer and help us determine which men with the disease really need to be treated. Until then we don't really have a good solution. That's why I find targeted therapy so appealing.

Getting specific

When describing clinical tests, doctors and researchers often use the terms sensitivity and specificity. Sensitivity is how well the test identifies a disease or condition in people who have it. Specificity is how well the test identifies those who do not have a disease or condition.

How do you treat just the tumor?

With cryotherapy. It involves freezing cancer cells with argon gas, delivered to the prostate via a needle injected into the perineum. The doctor can guide the needle to the cancerous area and monitor treatment with real-time ultrasound images generated by an ultrasound probe in the patient's rectum. During cryotherapy, the cells are frozen and thawed at least twice. When ice crystals form, they tear the cell membranes apart. Cells may also burst during the freezing and thawing process. [For more information about cryotherapy, see "Cryotherapy."]

Are there other types of targeted therapy?

Yes, but they aren't approved by the FDA; they are still experimental. One is HIFU, which stands for high-intensity focused ultrasound. HIFU sends a high amount of energy into the prostate through a probe inserted in the rectum. The energy beams, which enter the prostate at different angles, create heat at the point where they converge, damaging cells in just a few seconds. Sound waves also create vibrations in the tissues that further destroy the tumor. Because HIFU destroys only a small bit of tissue at a time, skin and noncancerous tissue remain unharmed. We use magnetic resonance imaging to view the prostate and see exactly where we are aiming the ultrasound. HIFU is not FDA-approved, so men can only have this procedure in the United States if they participate in a clinical trial. [For more information about HIFU, see "High-intensity focused ultrasound (HIFU)." For more details on targeted therapies, see "Focal therapies" and "Focal therapy for prostate cancer."]

Focal therapy for prostate cancer

Barqawi AB, Crawford ED. Emerging Role of HIFU as a Noninvasive Ablative Method to Treat Localized Prostate Cancer. Oncology 2008;22:123–29. PMID: 18409659.

Crawford ED, Barqawi A. Targeted Focal Therapy: A Minimally Invasive Ablation Technique for Early Prostate Cancer. Oncology 2007;21:27–32. PMID: 17313155.

Crawford ED, Wilson SS, Torkko KC, et al. Clinical Staging of Prostate Cancer: A Computer-Simulated Study of Transperineal Prostate Biopsy. BJU International 2005;96:999–1004. PMID: 16225516.

Photodynamic therapy [PDT], which has been used to treat skin cancer, shows potential as a focal therapy for the treatment of prostate cancer, too. During PDT, patients receive a photosensitizer. This is a light-sensitive chemical that accumulates in the target tissue and releases toxic, cell-killing substances when it's exposed to light. Optical fibers inserted into the prostate through catheters deliver the light [see Figure 17]. Newer, experimental photosensitizers seem to destroy tumors primarily by attacking the blood vessels that feed them.

Another still-experimental treatment for prostate cancer is called NanoKnife. In this procedure, two needles are inserted into the cancerous part of the prostate. An electrical current travels through and between the needles, killing the cancer. I hope to soon start working on a study using the NanoKnife and mapping biopsies.

Figure 17: Photodynamic therapy

Photodynamic therapy

During this treatment, light-sensitive chemicals accumulate in cancerous tissue. When exposed to light from optical fibers inserted into the prostate through hollow needles, the chemicals release toxic substances that destroy tumors (inset). Doctors monitor the procedure using transrectal ultrasound.

What is a mapping biopsy?

To formally diagnose cancer, a urologist will do a biopsy, which involves taking several bits of tissue, or cores, from different parts of the prostate, examining them under a microscope, and determining whether cancer is present. If cancer is present, a traditional biopsy will tell you roughly where the cancer is located, such as the anterior right side, but you don't know exactly where it is. And because only a small number of samples are taken, a cancer could be missed. For targeted therapy to work, you can't rely on a traditional biopsy. You have to have a mapping biopsy to know that you aren't missing small yet significant cancers.

To do a mapping biopsy, we use a template [see Figure 18] that was created to give patients brachytherapy, a type of radiation therapy. We take anywhere from 30 to 90 cores, depending on the size of the man's prostate, and record the precise location of each. Then we test the tissue, correlating the pathologic findings with a three-dimensional anatomical map of the prostate. Depending on the size, number, and location of any tumors, we can decide whether the patient is a candidate for targeted therapy or not.

Figure 18: Mapping biopsy grid

Mapping biopsy grid

Placed over the perineum, a grid like this one can aid doctors performing a mapping biopsy. Tissue samples are taken every 5 millimeters, front to back and side to side. (Each dot on the grid represents a hole through which a needle can be inserted.) This allows doctors to map the location of tumors in three dimensions and determine if a patient might be a candidate for focal therapy.

Thirty to 90 cores — that's a lot! Do patients have any side effects?

Mapping biopsies are not without side effects. The patient has to have a catheter in for three or sometimes four days, which can lead to an inability to empty the bladder, or urinary retention, once the catheter is removed. Blood clots can also form within the bladder, blocking urine flow. Sometimes there are scrapes on the scrotum. But none of my patients have had any serious side effects. It does seem that the bigger the prostate, the worse the side effects, so I've started having men with larger prostates — those estimated to be over 50 grams — take the drug dutasteride [Avodart] for three months before we do the mapping. The drug, which is used to treat benign prostatic hyperplasia, also called an enlarged prostate, helps shrink the gland.

Who is a good candidate for a mapping biopsy?

The ideal patient for a mapping biopsy is a man who is healthy, potent, and motivated to try an alternative treatment, and has a low-volume, stage T1c cancer with a Gleason score of 6. I might also add age to that list. Many doctors believe this therapy is better for older men, but I have many patients in their 50s who are interested in it.

How accurate are mapping biopsies?

In one small study I did that will soon be published, I performed a mapping biopsy on about 30 men when they had a radical prostatectomy. Afterward, we correlated the results of the mapping biopsies with the pathology reports from the whole mounts, meaning the tissue slices from the whole prostate that the pathologist examined under the microscope after it was removed. We actually found two cancers in the mapping biopsies that were missed on the whole mounts, including a small cancer with Gleason score of 8. And the mapping biopsies didn't miss anything that was detected by the whole mounts.

Given their level of accuracy, why aren't mapping biopsies routinely done?

They take a fair amount of time, and urologists aren't reimbursed very well for doing them. They can also lead to some minor complications. And many urologists aren't trained to do them.

What percentage of men who have a mapping biopsy could be effectively treated with targeted therapy?

I have found that about 40% of patients who have had a mapping biopsy have low-risk prostate cancers that could be treated with targeted therapy. The rest have cancer on both sides of the prostate or cancer that is more extensive or of a higher grade than first thought based on the original biopsy. But for the 40% who "qualify," targeted therapy could treat the cancer and limit complications like incontinence and impotence.

What findings on a mapping biopsy would qualify a patient for active surveillance?

The typical criteria for active surveillance apply: a small amount of low-grade, Gleason 6 cancer on one side of the prostate.

What are the challenges of targeted focal therapy?

Over the years, a lot of patients have come to me and said, "Doc, I want you to just take out part of my prostate, or treat just part of it." And I used to say, "You can't do that. This disease is multifocal — meaning it's in more than one spot in the prostate — you just can't go in and lop out part of the prostate."

But now we know that prostate cancer isn't multifocal in everybody. With mapping biopsies, we can locate the tumor or tumors and figure out exactly where treatment is needed. Down the line, there will also be better imaging tests — such as MRI or CT scans — that will allow us to really see the prostate well and see where the cancer is. We don't have that yet, unfortunately, so we have to rely on biopsies, which involve sticking a lot of needles into the prostate, and of course that isn't pleasant for the patient.

Any final comments?

Anyone who looks at the history of prostate cancer diagnosis and treatment will see that we've made a tremendous amount of progress over the past few decades. But we still don't know exactly which cancers need to be treated. Until we can do that reliably, I think we need to offer men something to control their cancer without destroying their quality of life. That's a role that targeted therapy can fill. I believe that up to 40% of currently diagnosed prostate cancers may be amenable to targeted therapy.

Focal therapies

In 2007, two teams of researchers, one in England and the other in the United States, published papers arguing in favor of testing focal therapy, in which only the tumor and a small margin of normal tissue around it are treated instead of the entire prostate gland. This approach, they say, would minimize damage to structures essential for sexual, urinary, and bowel function and allow for retreatment later on if necessary.

To support their thinking, the U.S. team pointed to a study showing that 38% of prostate tissue samples analyzed after radical surgery had a single cancerous lesion. In patients with multiple disease sites, or foci, 80% of the total tumor volume could be attributed to the largest cancerous spot, according to another study. Because the secondary tumors rarely have higher Gleason scores than the main tumor, the thinking goes that they are unlikely to affect overall disease progression. As a result, the researchers suggest targeting just the primary tumor (what doctors call the index tumor). Because they can reliably target a specific point, cryotherapy, HIFU, and radiation therapy can be used as focal therapies to attack the primary tumor.

Photodynamic therapy (PDT), which has been used to treat skin cancer, also shows potential as a focal therapy for the treatment of prostate cancer. During PDT, patients are given a photosensitizer, a light-sensitive chemical that accumulates in the target tissue. When it's exposed to light, the photosensitizer releases toxic substances that destroy tumor cells. (Optical fibers inserted into the prostate through catheters deliver the light.) Newer, experimental photosensitizers seek to destroy tumors primarily by attacking the blood vessels that feed them.

Since focal therapy does not treat the entire prostate, consistently finding and hitting the target area is essential. Thanks to dramatic improvements in imaging technologies, such as MRI, physicians can better determine whether cancer has spread to the seminal vesicles and can map a tumor's location more precisely than ever before.

Even so, a limited number of studies of focal therapy have been completed, and those that have been done included only a few dozen patients, used varying techniques, and lacked solid data on adverse effects (see "A selection of articles on focal therapies"). Proponents of focal therapies also assume that tiny secondary tumors won't become a problem later on, but that's not certain; in some cases, such tumors have metastasized. Then there's the possibility that cells from the primary tumor may have already spread; these micrometastases can escape detection with current technology. (Estimated accuracy rates for MRI in focal therapy range from 40% to 90%.) Incomplete treatment or a missed spot of cancer could have profound consequences. And although one would think that the extent and number of complications would be less with focal therapies than with whole-gland treatment, that isn't known for certain. (To see what one internationally respected investigator has to say about focal therapies, read "Targeted focal therapy for early-stage prostate cancer.")

A selection of articles on focal therapies

Ahmed HU, Pendse D, Illing R, et al. Will Focal Therapy Become a Standard of Care for Men with Localized Prostate Cancer? Nature Clinical Practice Oncology 2007;4:632–42. PMID:17965641.

Eggener SE, Scardino PT, Carroll PR, et al. Focal Therapy for Localized Prostate Cancer: A Critical Appraisal of Rationale and Modalities. Journal of Urology 2007;178:2260–67. PMID: 17936815.

Hormone therapy

Androgens, the family of male sex hormones that includes testosterone, function as a fuel for growth in normal development. However, they can also drive the development and progression of prostate cancer. Androgen-deprivation therapy, also called hormone therapy, can fight prostate cancer because it dramatically reduces levels of testosterone and other androgens (see Figure 19). Hormone therapy is a treatment option for men who

  • have cancer that has spread beyond the prostate

  • have cancer that is confined to the prostate but need to boost the effectiveness of radiation therapy or to shrink the size of the prostate before brachytherapy

  • have a rising PSA after initial treatment with surgery or radiation therapy, indicating that the cancer may have recurred.

Figure 19: 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.

How hormone therapy affects the androgen cascade

The androgen cascade

  1. The hypothalamus releases pulses of luteinizing hormone–releasing hormone (LHRH), which signals the pituitary gland to crank out luteinizing hormone (LH).

  2. LH travels through the bloodstream. When it reaches the testicles, it triggers the action of specialized cells that secrete testosterone into the bloodstream.

  3. 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.

GnRH antagonists jam 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 the testicles do not make testosterone.

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 receptors located in the prostate cancer cells. Stimulation of these receptors allows cells to grow. By blocking this stimulation, anti-androgens prevent prostate cancer cell growth.

In the past, hormone therapy meant the surgical removal of both testicles, a procedure known as orchiectomy. Because more than 90% of androgens are produced in the testicles, orchiectomy immediately ceased production of most of the hormones fueling the growth of prostate cancer cells. But because many men find the idea of having their testicles removed difficult to accept and because the procedure can't be reversed, doctors now use drugs to dramatically lower androgen levels and slow prostate cancer (see Table 7). Doctors often recommend injectable drugs — primarily luteinizing hormone–releasing hormone (LHRH) agonists. Gonadotropin-releasing hormone (GnRH) antagonists and anti-androgens, two other classes of drugs, are occasionally used.

Table 7: 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 antagonists

abarelix (Plenaxis), degarelix (Firmagon)

Hot flashes, sleep disturbances, pain, dizziness, headache, nausea, fatigue, small chance of a serious allergic reaction.

Abarelix is not commercially available in the United States. Degarelix is given monthly via injection.

Anti-androgens

bicalutamide (Casodex, generic), 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.

Antifungal

ketoconazole (Nizoral)

Nausea, fatigue, swelling, skin rash, abnormal liver function.

Rapidly lowers blood levels of testosterone; used with hydrocortisone. Should not be taken with alcohol.

Investigational drugs

abiraterone, MDV3100

For abiraterone, abnormal liver function.

For MDV3100, fatigue, nausea, labored breathing, and appetite loss.

Available only through clinical trials.

The injected LHRH agonists inhibit the production of luteinizing hormone in the pituitary gland. Because luteinizing hormone stimulates testosterone secretion in the testicles, 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, formulations are available that 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 to four weeks. 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, may also be prescribed to block the effect of androgens produced in the adrenal glands. (About 5% to 10% of male hormones are produced in these glands.) Anti-androgens prevent these residual male hormones from latching on to receptors on prostate cells.

Two GnRH antagonists, abarelix (Plenaxis) and degarelix (Firmagon),* block the release of luteinizing hormone just as LHRH agonists do, but they do not trigger a testosterone surge. Although available in Europe, abarelix is not available in the United States. Instead, doctors can prescribe degarelix, which works in the same way and has similar side effects. It is injected monthly.

*Editor's note: Editor in Chief Marc B. Garnick, M.D., helped develop the GnRH antagonist abarelix. He serves as a consultant to Specialty European Pharma, which is marketing abarelix in Europe, and to Ferring Pharmaceuticals, the manufacturer of degarelix.

Hormone therapy produces the same benefits as orchiectomy, but patients must 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 hormone therapy. 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. Also, reduction in bone density and muscle mass occurs in some patients, and breast enlargement can be a significant problem. 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.

Evidence supports the combined use of hormone therapy and radiation. A 2004 study in The Journal of the American Medical Association found that combining these two therapies was especially effective 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 a median period of four-and-a-half years, the men who received radiation plus hormone therapy had significantly higher survival rates and significantly lower risk of relapse than men who received radiation only (see "Hormones and radiation"). Additional studies on the long-term benefits of combined treatments are under way.

Hormones and radiation

D'Amico AV, Manola J, Loffredo M, et al. 6-Month Androgen Suppression Plus Radiation Therapy vs. Radiation Therapy Alone for Patients with Clinically Localized Prostate Cancer: A Randomized Controlled Trial. Journal of the American Medical Association 2004;292:821–27. PMID: 15315996.

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 for men with advanced cancer who no longer respond to hormone therapy, a situation referred to as androgen-independent, or 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 (see Table 8) 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.

Table 8: Chemotherapy for advanced prostate cancer

Drug name*

Common side effects

Comments

docetaxel
(Taxotere)

Hair loss, nausea and vomiting, drop in blood cell counts, numbness and tingling (usually in the feet)

These anticancer drugs may be used alone or in combination with other chemotherapeutic agents, such as estramustine and carboplatin. Studies are looking at the effect of combining these agents with other types of drugs, such as those that target blood vessels feeding the cancer. Docetaxel can extend survival. Although not specifically approved for the treatment of prostate cancer, paclitaxel can ease symptoms.

paclitaxel
(Taxol)

Hair loss, nausea and vomiting, fatigue, drop in blood cell counts, numbness and tingling in hands and feet (usually after long-term use)

cabazitaxel (Jevtana)

Drop in blood cell counts, diarrhea, fatigue, nausea, vomiting, constipation, weakness, kidney failure

In combination with the steroid prednisone, cabazitaxel is approved for use in men who no longer respond to docetaxel. It can extend survival.

mitoxantrone
(Novantrone)

Nausea and vomiting, hair loss, fatigue, drop in blood cell counts

This FDA-approved drug is often used in men who do not respond to docetaxel; eases symptoms.

vinorelbine
(Navelbine)

Nausea, vomiting, fatigue, constipation, diarrhea, tingling in hands and feet, hair loss, muscle aches, drop in white blood cells

Increased risk of infection; fever and chills should be reported to a physician. Although not specifically approved for the treatment of prostate cancer, it can ease symptoms.

carboplatin
(Paraplatin)

Low blood counts, nausea, vomiting, taste changes, hair loss, weakness, constipation, diarrhea

Used as a single agent and in combination with paclitaxel and estramustine. Also used as a second-line therapy for patients who have become resistant to docetaxel. Although not specifically approved for the treatment of prostate cancer, it can ease symptoms.

estramustine
(Emcyt)

Blood clots, nausea and vomiting, fatigue, headache, drop in blood cell counts

Often combined with other agents in clinical trials, but the risk of blood clots and other complications make estramustine unlikely to become a standard treatment. Approved for use in prostate cancer patients to ease symptoms.

*This is a partial list, reflecting the more promising chemotherapeutic agents in clinical practice and in clinical trials. It does not include all agents or those in early stages of development. Some have not been approved by the FDA for the treatment of prostate cancer and may not be covered by health insurance. Drugs are listed in order of approximate frequency of use.

Vaccines and other emerging therapies

Unlike vaccines that prevent infections, prostate cancer "vaccines" help fight advanced prostate cancer that no longer responds to other therapies by revving up the body's immune system. One such vaccine, sipuleucel-T (Provenge), is now commercially available (see "Prostate cancer vaccine approved by FDA"). This treatment involves removing white blood cells from the patient's blood and exposing them to a protein made by prostate cancer cells called prostatic acid phosphatase (PAP). The cells are then returned to the patient. This process is repeated twice, at two-week intervals, for a total of three infusions. Cells that have been exposed to PAP prompt other immune system cells to attack prostate cancer cells.

A second prostate cancer vaccine, PROSTVAC-VF, which is still under development, works differently. Instead of using a patient's cells, it uses genetically engineered relatives of the smallpox virus, which produce slightly irregular versions of PSA and three other molecules to spur a more vigorous immune system attack on cancer cells. In a randomized, controlled phase II trial of PROSTVAC-VF, 82 men whose cancer no longer responded to hormone therapy received the vaccine; 40 men in the control group received a placebo. After three years, 30% of the patients in the vaccine group were alive, versus 17% of those in the control group. The median length of survival in the vaccine group was 25.1 months, compared with 16.6 months in the control group, an increase of 8.5 months (see "PROSTVAC-VF results"). Reported side effects of the vaccine included fatigue, fevers, and nausea. Investigators are planning a larger phase III trial to further evaluate the vaccine's effectiveness.

To learn more about the vaccines and other promising therapies currently in development, read the roundtable discussion "Emerging therapies for advanced prostate cancer."

PROSTVAC-VF results

Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer. Journal of Clinical Oncology 2010;28:1099–105. PMID: 20100959.

Roundtable discussion: Emerging therapies for advanced prostate cancer

"Vaccines," new chemotherapies, and other agents are finally becoming viable treatment options

Medical oncologists used to have little to offer patients with advanced prostate cancer, especially those whose disease progressed despite hormone therapy. Just one type of chemotherapy, docetaxel (Taxotere), prolonged survival in clinical trials and was approved by the FDA specifically for the treatment of prostate cancer.

In 2010, three drugs for patients with advanced disease made headlines. First, the prostate cancer "vaccine," sipuleucel-T (Provenge), which stimulates the body's immune system, gained FDA approval in April. A few months later, the chemotherapy drug cabazitaxel (Jevtana) received approval, too. And by summer's end, phase III clinical trials of another drug, abiraterone, showed it could help men live longer while causing them relatively few side effects.

To highlight these pharmacological advances and find out about other therapies that could eventually make their way into clinical practice, the editors of Harvard Medical School's 2011 Annual Report on Prostate Diseases invited two highly regarded medical oncologists to participate in a roundtable discussion of new and emerging drugs — and which patients are most likely to benefit from them:

  • Glenn J. Bubley, M.D., a medical oncologist and director of genitourinary oncology at Beth Israel Deaconess Medical Center in Boston. He has been a principal investigator for studies looking at cancer cell biology and the effectiveness of therapies in prostate cancer patients. He is an associate professor of medicine at Harvard Medical School.

  • William Oh, M.D., chief of hematology and oncology at the Tisch Cancer Institute at Mount Sinai School of Medicine in New York City. A medical oncologist, he has served as the lead investigator for numerous studies on therapies for prostate cancer, including investigational chemotherapy regimens.

Marc B. Garnick, M.D., editor in chief of this report, moderated the session.

What do you think about the proliferation of new drugs to treat advanced prostate cancer?

OH: This is a very exciting time because we are seeing more drugs being approved, particularly for patients with castration-resistant prostate cancer, and that's always welcome. What's also exciting is that these drugs are coming as a result of better knowledge of what's going on with prostate cancer. We're really starting to capitalize on a greater understanding of the biology of advanced prostate cancer.

Provenge has generated a lot of discussion. What are your thoughts on this drug?

BUBLEY: Based on eligibility requirements, many patients qualify for the drug. But there are a number of logistical barriers to offering it, and the cost to society will be dramatic.

OH: What's so interesting about Provenge is that it reliably prolonged survival in randomized studies, but we don't know why patients lived longer. [The median survival time increased by over four months.] It doesn't induce a clinical response that we can see, and it doesn't necessarily delay progression of the disease, so how are these men living longer? In medicine, we like to understand why something works so that we can explain what we're doing and why to patients — and so that we can develop better drugs. With Provenge, we don't fully understand what it is doing to the immune system, but there are many things in medicine we don't fully understand. I think the safety profile is clear, so I am going to offer it to patients for whom it's indicated. If I have a drug that might help someone, I'm going to take advantage of it.

Who's the ideal candidate for Provenge?

BUBLEY: It's approved for men with metastatic, castration-resistant prostate cancer who are asymptomatic or minimally symptomatic. These were the type of patients who were included in the trial. Because Provenge boosts the immune system, patients have to live long enough to develop a robust immune response. If a patient has already received a tremendous amount of therapy or is quite ill, he is much less likely to benefit from this type of therapy. That has led a lot of people to ask whether it should be given even sooner, such as before metastases develop, when the PSA rises, right after surgery or radiation, or even in lieu of surgery or radiation. But the problem is that the drug hasn't been adequately studied in any of those earlier disease states, and so there's no evidence that patients will benefit. Using Provenge in these patients would be an off-label use, so it would not be covered by insurance. Given the expense,* I don't think patients with earlier-stage disease will want to receive it.

*Editor's note: At the time of publication, a full course of Provenge cost $93,000.

Although we aren't sure how much insurance companies will reimburse or what copays will be, I spoke to one oncologist who felt that the survival benefit was marginal and not worth the cost, so his practice won't be offering it.

BUBLEY: The survival advantage with Provenge is actually better than with the chemotherapy drug docetaxel [Taxotere], and he likely offers that, because until Provenge was approved, there wasn't another drug that extended survival in patients with advanced prostate cancer. So, that argument really holds no water. However, to be fair to that oncologist, there are no biomarkers to predict who is going to respond to the drug. We also don't have any intermediate endpoints, such as PSA levels, to tell who will benefit. But because it's safe enough, we may have to offer it to everyone who meets the criteria, but this is not the way we would prefer to treat patients.

OH: When it comes to castration-resistant prostate cancer, very few drugs have shown a survival benefit. Docetaxel continues to be one we all use, but the median survival benefit is actually longer with Provenge, and patients have fewer side effects. In many ways, this is the ideal therapy for patients with advanced prostate cancer because it's boosting their immune systems, helping them live longer, and causing very few side effects. And the treatment is over in just four weeks.

The cost issue is a difficult one. As a society, we're struggling to figure out how to pay for our health care. Unless we're going to ration new therapies, we need to decide whether drugs are beneficial enough to give regardless of cost. But as a physician, I cannot use cost as a reason to give or not give a particular treatment to a patient. I think the people who are struggling with whether or not to offer this therapy are struggling with it because we find it very unsatisfying when we don't understand how something works. I think that's what is actually underlying some of the skepticism about this drug.

The fact that we don't fully understand the science behind Provenge leaves a lot of other practical questions unanswered — the timing of subsequent therapy, for example. When is it safe to give chemotherapy? Should you give steroids with chemotherapy? If so, is it better to take chemotherapy with steroids after one month? Three months? Six months? The immune consequences of subsequent treatments in these patients could be quite profound, especially the widespread use of immunosuppressants such as steroids. And yet, we don't understand any of that. We need to understand those nuances, because that may be the difference between benefit and no benefit with drugs like Provenge.

What happens if the preparation fails or the manufacturer doesn't get enough of the specific type of immune system cells it needs from the patient to make the vaccine?

OH: I don't think that's been a problem so far. But if they can't get enough cells to actually make a vaccine, then you can't get it. You'd have to move on to the next therapy.

Can any oncologist write an order for Provenge?

OH: No. The issue is capacity. Dendreon Corp., the manufacturer, has estimated that they can only treat 2,000 patients in the first year, but there are many more patients who are candidates for it. Dendreon is building factories to produce the vaccine, but right now, only facilities that took part in the clinical trials will be able to administer the drug. When they can make enough of it, it will be more widely available. We've only treated about 10 patients here in New York [at Mount Sinai] outside of the clinical trial.

BUBLEY: Even the medical centers that offer it are having the logistical challenges that I mentioned earlier. People have to go to a blood bank or another facility to have their blood drawn, and then that's sent off to make the vaccine. When the product comes back, where does it go? To the blood bank? It's not blood. Who infuses it? It's not exactly a stem cell therapy, so the stem cell professionals don't want to handle it. It's not a drug, so it doesn't fall under the realm of the pharmacy.

OH: Infusing it isn't hard, so urologists' offices could handle it, but they aren't usually set up for drug infusions. Also, if the hospital contracts the work to a blood bank in the community, a system has to be set up for billing. I think all of these things will be worked out, but it's going to take time to get the processes in place.

Let's move on to cabazitaxel, which was approved by the FDA in June 2010. What are your thoughts on this chemotherapy drug?

OH: I was shocked at how effective it was in the clinical trials. It's a next-generation taxane [first-generation taxanes are docetaxel and paclitaxel], so it wasn't a surprise that it would work against prostate cancer, but I don't think people expected much of it. I think it was a real shocker when researchers announced at the American Society of Clinical Oncology meeting in March 2010 that it had a three-month survival benefit in men with metastatic prostate cancer who had already been treated with docetaxel. Those findings were from a phase III clinical trial in which it was compared to mitoxantrone [Novantrone], a drug already approved by the FDA, and the statistically significant increase in survival is what led to the drug's approval. It can have some serious adverse effects, such as a drop in white blood cells, which can open patients up to infections. That happened in 7.5% of the patients in the trial who took cabazitaxel, but in only 1.3% of the patients who took mitoxantrone. But for the right patients, it's clearly a better drug than any of the other chemotherapies.

So you would prescribe cabazitaxel before mitoxantrone?

OH: Yes. Because it was compared head-to-head against mitoxantrone and convincingly beat it. But I would only consider it in patients who are similar to the patients who received it in the study — those whose organs were functioning well and had adequate white blood cell counts.

Is there still a place for mitoxantrone in clinical practice?

BUBLEY: I think we will still use it because patients with castration-resistant prostate cancer can live a long time and may need other therapy. We'd probably start with docetaxel, and then move on to cabazitaxel, and then mitoxantrone, and then to any investigational agents.

OH: Some physicians might still use mitoxantrone, but it's not going to be the de facto second-line therapy that it has been.

How is it that this taxane can be so effective when another taxane, docetaxel, stops working?

BUBLEY: Patients eventually become resistant to docetaxel. We aren't sure why their cancers stop responding to it, but it might be that the drug has a hard time staying inside cancer cells. Cabazitaxel has a slightly different structure, so it might be less affected by some of the resistance mechanisms that affect docetaxel. Nonetheless, patients' cancers will eventually become resistant to cabazitaxel as well.

OH: One of the concerns with this study was that some of the patients who received cabazitaxel might not have been truly taxane-resistant. Up to a quarter of the participants had not received a significant dose of docetaxel or had not received it for several months. So was this truly a taxane-resistant population? Would some of them have responded to docetaxel if it were tried again? We don't know, but in the end, many physicians will use cabazitaxel because when a patient is truly taxane-resistant, there are no other options of significance. And in the end, I think it appeared to be a minority of the patients who either were undertreated with docetaxel or were not progressing while on docetaxel or soon after. So cabazitaxel will be my standard second-line chemotherapy.

Results of a phase III trial of abiraterone were just announced [see "Experimental drug extends survival in advanced prostate cancer"], and it looks like this drug, which affects the hormones that fuel prostate cancer, will be submitted to the FDA for approval.

BUBLEY: I think this is an exciting development. Abiraterone may benefit more patients, its beneficial effects may be more prolonged than ketoconazole's, and it's much better tolerated.

OH: Abiraterone builds on a very solid biological foundation of what's driving castration-resistant prostate cancer, namely that testosterone continues to feed and support the tumors. This drug clearly blocks some of that testosterone and induces a fairly robust and durable response. It's not a curative treatment, and it does have side effects, such as abnormal liver function, increases in blood pressure, and other cardiovascular effects. But if it gets approved, it will be a big deal for patients. Any therapy that will control their cancers with fewer side effects than ketoconazole would be welcomed.

How does abiraterone work?

BUBLEY: To make androgens, the body converts cholesterol into the hormones pregnenolone and progesterone. They are converted to DHEA. DHEA is converted to androstenedione, and that's converted to dihydrotestosterone [DHT]. If you can inhibit that pathway and not produce androstenedione, you can inhibit the production of androgens across the board, wherever they are made — in the testis, in the adrenal gland, or even in tumor cells themselves. Normally, to get to DHEA, you need an enzyme called CYP17. Without CYP17, you cannot get DHEA or androstenedione. Abiraterone blocks CYP17. Ketoconazole blocks a variety of enzymes, but abiraterone blocks just CYP17, so it does a better job. That's why I think the need for ketoconazole will be relatively limited after abiraterone gets approved.

When do you think that might happen?

OH: I have heard spring of 2011.

Will patients have to be treated with docetaxel prior to getting abiraterone?

BUBLEY: There are two phase III randomized trials: one included patients who had been treated with docetaxel — that's the one we have findings from — and the other included patients who haven't yet received treatment with docetaxel. I'm not sure when we'll have data from the second trial.

Do you think there should be a head-to-head comparison of abiraterone and ketoconazole?

BUBLEY: That will never happen.

OH: Ketoconazole is not an approved drug for advanced prostate cancer. And the company that developed abiraterone has no incentive to compare their drug to an unapproved drug that might work. So a head-to-head trial isn't going to happen.

Is TAK-700 the same drug as abiraterone?

BUBLEY: TAK-700 hits the same targets as abiraterone, but it's a different drug. It's being studied in exactly the same way as abiraterone. It's not as far along though. Phase II studies of TAK-700 are ongoing.

Another experimental drug, MDV3100, also affects androgens.

OH: That's correct. It works like an anti-androgen [see Figure 19]. Anti-androgens, like bicalutamide [Casodex] and flutamide [Eulexin], have been around for a long time. They block the interaction of DHT with the androgen receptors in prostate cancer cells, and that prevents the cells from growing. MDV3100 is much more potent than bicalutamide and the others because it not only blocks the androgen receptors, but also destroys them, so it works on multiple levels.

In phase I and phase II MDV3100 studies, which have tested different doses, the majority of patients with castration-resistant prostate cancer [see "More than semantics"] who received it responded to it, whether or not they had been treated with chemotherapy. The real issue is whether the patients will live longer. There are two ongoing phase III studies — one using MDV3100 before chemotherapy and the other one using it after chemotherapy — so we'll find out whether it improves survival and in which patients.

More than semantics

Many people use "castration-resistant prostate cancer" and "hormone-refractory prostate cancer" interchangeably. Hormone-refractory prostate cancer implies that the cancer no longer responds to hormone therapy, but the fact that prostate cancer responds to drugs like abiraterone and MDV3100 shows that the tumor is still "hormone sensitive." As a result, the experts interviewed here prefer the term castration-resistant prostate cancer.

Let's move on and talk about PTEN, a gene that may suppress prostate cancer.

BUBLEY: We've found that a lot of patients with metastatic prostate cancer are PTEN deficient, meaning that they have a mutation in the PTEN gene. PTEN normally keeps the cancer-causing PI3K pathway in check, so when PTEN is "lost," cancer cells grow faster. PI3K also activates other genes that seem to play a role in prostate cancer, namely AKT and mTOR.

We've tried to inhibit mTOR, but we really saw no effect at all with that. You could try inhibiting the PI3K pathway — a route or series of steps in a particular direction that cancer takes in order to grow. There's a view out there that inhibiting the PI3K pathway by itself won't be sufficient and that you'll need to inhibit a parallel pathway called MEC. Experiments looking at that issue are already under way.

OH: I think a lot of the preclinical biology suggested that blocking the PI3K pathway is really critical. But we have not tested the new PI3K inhibitors in the clinic yet in phase II studies, so it's too soon to say if blocking this pathway will be effective. As Dr. Bubley mentioned, studies with mTOR inhibitors have been disappointing. I think that's a reminder that laboratory models for predicting what is driving these cancers may not translate into effective treatment for patients. Our models certainly aren't perfect. And there could also be more than one pathway. If you block one pathway, the cancer might go right around it and use an alternate pathway to get what it needs to grow. The idea that we can stop prostate cancer by blocking a single pathway may be naïve; we may need to use combinations of drugs to block multiple pathways in order to have a clinically meaningful benefit.

Are you moderately excited about PI3K inhibitors or not excited at all?

OH: I think moderately is the right word. When we bring something into the real world that we were enthusiastic about in the laboratory, we are often humbled. Some of the most promising drugs turn out to be disappointing. On the flip side, drugs for which there was tremendous skepticism, such as Provenge and cabazitaxel, have turned out to be quite successful. That's why we have to study drugs and their targets in people. The mice get us only so far.

Finally, some studies have shown that men with diabetes are less likely to develop prostate cancer than the general male population, perhaps because they take a drug called metformin, which affects insulin levels. How is it that possible?

BUBLEY: A retrospective analysis of who gets prostate cancer showed that people who had been on metformin were less likely to get prostate cancer than those who weren't diabetics or who had been treated with insulin or other diabetes drugs. I thought that was just incredible.

OH: There have been a lot of strongly suggestive data about the relationship between the onset and progression of prostate cancer and metabolic changes. But it's really hard to take this information and design clinical trials. I don't think our understanding of how metabolic changes might be driving cancer is sufficient. We're not far enough along to know exactly when to use which drug at which time and on which occasion to go down this road. It's certainly exciting and suggestive epidemiologic data, but I think we have to be very cautious and certainly not encourage people to use some of these drugs when they don't have an indication to do so.

Is there clinical research under way on metformin?

BUBLEY: There is an interesting clinical trial under way for patients with castration-resistant prostate cancer and rising PSA levels, but whose disease hasn't metastasized. They will be given a full dose of metformin. The hypothesis is that patients who are prediabetic or have high risk levels at the start of the trial will have the greatest benefit in terms of PSA outcome. It's an open phase II trial. Metformin is the only FDA-approved agent for the treatment of diabetes that lowers insulin levels. It's surprising to me that you can give metformin to a patient without diabetes and not have him become hypoglycemic. If the hypothesis is correct, metformin will only be effective in patients who are prediabetic, if there's any effect.

Will it be preventive?

BUBLEY: This study is looking at reductions in PSA levels in patients who have prostate cancer, so we won't learn anything about its prevention ability.

What else is out there? What do you see in your crystal ball over the next 10 years?

BUBLEY: Based on what we've seen with Provenge and its ability to harness the immune system, I think other immune therapies will start to come to the fore. One called PROSTVAC has been shown to have a survival advantage roughly twice that derived from Provenge. Perhaps this or other immune therapies could be given with Provenge or even after Provenge stops working. The field is wide open. I think that we'll see more and more agents over the next 10 years that are going to extend patients' survival dramatically.

Ask a doctor

How do I know whether I am a candidate for sipuleucel-T (Provenge)?

To be a candidate for this vaccine, you must have

  • prostate cancer that no longer responds to androgen deprivation (hormone therapy)

  • cancer that has spread (metastatic disease)

  • relatively normal activity levels.

If you are on chemotherapy, you need to stop receiving it at least three months before starting sipuleucel-T. You cannot take steroids or any other immune-suppressing medications. In general, doctors avoid prescribing sipuleucel-T to patients who take more than a small dose of narcotics for cancer-related pain. Such patients may have very advanced cancer, making them unlikely to benefit from the slow-working vaccine.

As of fall 2010, approximately 50 medical facilities in the United States had been approved to administer sipuleucel-T. Each will probably treat just two or three patients a month until the vaccine's manufacturer, Dendreon Corp., boosts its production capability in early 2011. Some medical centers have a waiting list for qualified patients.

A word of warning: although Medicare and some private insurance companies have covered the vaccine's $93,000 cost, confirm coverage with your insurer before starting treatment.

— Mary-Ellen Taplin, M.D.
Medical Oncologist, Dana-Farber Cancer Institute

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 diagnosis, 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 (see "Studies of impotence and incontinence").

Incontinence. Urinary incontinence after prostate cancer treatment is less common than erectile dysfunction. 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. Two years after treatment, only 3.5% of them reported leakage. 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 (see "Studies of impotence and incontinence").

Studies of impotence and incontinence

Potosky AL, Davis WW, Hoffman RM, et al. Five-Year Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: The Prostate Cancer Outcomes Study. Journal of the National Cancer Institute 2004;96:1358–67. PMID: 15367568.

Potosky AL, Legler J, Albertsen PC, et al. Health Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: Results from the Prostate Cancer Outcomes Study. Journal of the National Cancer Institute 2000;92:1582–92. PMID: 11018094.

Late-breaking NEWS!

Advisory panel rejects BPH drugs for cancer prevention

In December 2010, an FDA advisory panel overwhelmingly agreed that the drugs finasteride (Proscar, generic) and dutasteride (Avodart) should not be prescribed to prevent prostate cancer. GlaxoSmithKline, the maker of Avodart, is seeking FDA approval to label its product as a prostate cancer-prevention drug.

Belonging to a class of drugs called 5-alpha-reductase inhibitors, finasteride and dutasteride are approved for the treatment of urinary symptoms associated with BPH (benign prostatic hyperplasia). Clinical trials conducted over the past several years concluded that both drugs could reduce the overall risk of prostate cancer by about 25% compared with a placebo. But the same studies also found slightly increased rates of high-grade cancers in men who took the drugs compared with those who took a placebo.

In subsequent analyses, investigators and the drugs' manufacturers tried to demonstrate that the drugs didn't actually cause more aggressive tumors. Rather, they concluded that because the drugs shrink the prostate, the biopsy needle was more likely to strike cancerous tissue if it was there. In short, they said, the drugs weren't causing the cancers but making them more likely to be found. (See "Chemoprevention" and "Hesitation on Chemoprevention.")

Panel members weren't convinced. Concerned that otherwise healthy men might develop aggressive prostate cancers, they voted that the drugs' risks outweighed their prevention potential. The FDA does not need to follow the recommendation of its advisory group, but it often does so. As of Dec. 22, 2010, the date this publication went to press, the FDA had not yet issued its final ruling, which will be posted on www.HarvardProstateKnowledge.org.

Men who take finasteride or dutasteride for BPH should know that these drugs, when taken for several years, may slightly increase their risk of developing high-grade prostate cancer. They may want to discuss other treatment options with their doctors, as simply stopping the drugs may cause BPH symptoms to return.

Thoughts from an FDA advisory panel member

Editor in Chief Marc B. Garnick, M.D., served as a voting member of the FDA panel that reviewed data on finasteride and dutasteride. He comments:

"The advisory panel weighed a great deal of evidence about whether the increased number of high-grade cancers was due to the shrinkage of the prostate gland induced by finasteride or dutasteride. Ultimately, a detailed and rigorous analysis didn't support this conclusion, the panel decided. While there are several possible interpretations, one analysis suggested that 60 men would have to be treated for four to seven years with either finasteride or dutasteride to prevent one intermediate-risk prostate cancer. But for every 200 men treated during the same time period, one additional case of high-grade cancer might emerge. The advisory panel felt that this risk outweighed the potential benefit, leading members to vote overwhelming against recommending these drugs for the prevention of prostate cancer. However, the vote was nonbinding, and the FDA's final ruling may differ."

Author: Harvard Health Publications
Date Last Reviewed: 1/1/2011
Date Last Modified: 2/24/2011
Copyright Harvard Health Publications