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Special Health Reports


2012 Annual Report on Prostate Diseases

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

4. Prostate cancer

What you need to know at every stage of the disease

Prostate cancer is the second most commonly diagnosed cancer in men in the United States, and the second-leading cause of cancer death. The American Cancer Society estimates that in 2011, 240,890 men were diagnosed with the disease and 33,720 died of it. However, more than 90% of prostate tumors are detected before the cancer has spread — so most men can expect to survive the disease. According to the most recent data from the American Cancer Society, nearly 100% of men diagnosed with prostate cancer are still alive five years after diagnosis, 95% are alive at the 10-year mark, and 82% are alive at the 15-year mark.

Moreover, prostate cancer death rates have been decreasing since the mid-1990s. Some experts think the drop in prostate cancer deaths may be due to aggressive screening and improved treatment; others believe it reflects a generally healthier diet, the use of cholesterol-lowering statins (which might also reduce prostate cancer risk), or some unknown factor.

This mix of good and bad news speaks to one of the central dilemmas facing men diagnosed with prostate cancer today: many prostate cancers are slow-growing and may never reach the point of becoming dangerous. 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 experienced no ill effects.

The hard part is to determine which cancers are life-threatening and which are not, because there are no straightforward diagnostic tests to provide this information. Most men diagnosed with prostate cancer today learn they have the disease after a blood test that reveals abnormal levels of prostate-specific antigen (PSA), followed by a biopsy that finds cancer. Few men have had symptoms of prostate cancer, such as blood in the urine or pain while urinating. Yet once diagnosed, most men choose to undergo treatment — prompting worries that too many men are being treated for prostate cancer and risking life-threatening and life-altering complications. This concern about overtreatment is why the U.S. Preventive Services Task Force recommended in 2011 against routine PSA screening in healthy men (see "Consensus builds against routine PSA screening").

The year 2011 also yielded surprises in terms of our understanding about what may cause prostate cancer and how to prevent it. New research suggests that testosterone, once viewed as fueling prostate cancer growth, might not be as harmful as people thought (see "The testosterone paradox"). Meanwhile, two prevention strategies that once looked promising — the use of 5-alpha-reductase inhibitors and vitamin E supplements to reduce the risk of prostate cancer — actually seem to increase risk of high-grade prostate tumors (see "A setback for chemoprevention" and "Vitamin E supplements may increase risk").

If you're confused, you're not alone. But keep in mind that prostate cancer's slow growth can be beneficial: unlike cancers that develop rapidly, prostate cancer usually gives you plenty of time to sort through all the information and make treatment decisions. As surprising as this may seem, those decisions might mean no treatment at all.

What causes prostate cancer?

No one knows precisely what causes the disease, although researchers have identified some risk factors (see next section). Much of the research focus has been on genetic alterations that may initiate the development and speed the progression of prostate cancer. Researchers are studying cells to learn what damages their DNA and why some cells, once damaged, can repair themselves while others do not.

This is not a situation unique to prostate cancer. A person's genes play a role in the development of any cancer. 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. Those 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.

Experts estimate that inherited mutations cause only about 5% to 10% of prostate cancers, but interest remains strong in this field because the findings could one day enable clinicians to determine which men have aggressive cancers and which do not. 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. In 2011, researchers reported that they had identified alterations in five genes — LEPR, CRY1, RNASEL, IL4, and ARVCF — that together significantly increase the risk of aggressive prostate cancer. (Men with four or five of the genetic variants were 50% more likely to die of prostate cancer than those with two or fewer.) And a consortium announced that it had mapped the complete genome of prostate cancer in seven men with advanced cancer — and in doing so had identified new types of genetic alterations that may add to the knowledge of how prostate cancer begins and progresses.

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, which can increase cell proliferation, have a higher chance of developing prostate cancer than men with normal levels of the hormone.

The testosterone paradox

Testosterone is the hormone that gives men some of their most "manly" qualities, such as a deep voice, large muscles, and facial and body hair. It stimulates the growth of genitals at puberty, plays a role in sperm production, fuels libido, and contributes to erections. It also fosters the production of red blood cells, boosts mood, and aids thinking ability (cognition).

For a long time, researchers also thought testosterone had a dark side when it came to prostate cancer. The traditional view, going back 70 years, was that testosterone was a hormonal fuel that promoted the growth of cancer in the prostate. As such, high testosterone levels were seen as a culprit, possibly causing prostate cancer development and certainly contributing to its spread. Experts thought that's why cutting off the "fuel supply" — by administering androgen deprivation therapy, which reduces levels of testosterone — was such an effective treatment for prostate cancer. And that's why men with prostate cancer, or those who had undergone treatment for it in the past, were advised to avoid testosterone replacement therapy, lest they risk a recurrence of the cancer.

But in the past few years, some research has challenged many of these tenets. Although testosterone promotes prostate cancer growth in laboratory cell lines and in some animal studies, several large prospective studies that have evaluated testosterone replacement therapy in men have not found an increased risk of prostate cancer. An additional small study found that testosterone replacement therapy did not fuel cancer growth in men with mild to moderate prostate cancer who chose active surveillance.

Not everyone is convinced, however. First of all, the data remain sparse and studies have been short-term in nature. (The study suggesting that testosterone replacement was safe for men on active surveillance involved only 13 men who were followed for an average of 2.5 years.) Second, history provides an important cautionary note: hormone replacement therapy was once assumed to be safe in women, until long-term studies involving thousands of women proved that assumption wrong. Finally, one of the most effective treatments for prostate cancer is hormone therapy — also known as androgen deprivation therapy — which reduces testosterone levels. So if a reduction in testosterone can be used to treat prostate cancer, how could elevating testosterone be harmless?

Dr. Abraham Morgentaler — an editorial board member of this publication — has posited the "prostate saturation model" to explain this seeming paradox. According to his model, prostate cancer cells do need a certain amount of testosterone in order to grow — just as a houseplant needs a certain amount of water to thrive. That's why drastically reducing testosterone levels through hormone therapy can keep existing prostate cancer from growing. But Dr. Morgentaler believes that normal prostate cells, and even slightly abnormal "low-grade" cancer cells, seem to have a saturation point — imposed by the limited number of receptors they have for testosterone — and are not affected as levels of this hormone increase.

To further complicate matters, however, other research suggests that prostate cancer cells themselves may produce their own testosterone. Such "intracrine" production acts to promote tumor growth. Thus, a man's blood levels of testosterone may be low, but the prostate tumor itself may be awash in this hormone.

Clearly, much more needs to be learned about the relationship between testosterone and prostate cancer. In the meantime, it is probably best to be cautious with respect to testosterone replacement therapy.

Sources: Brand TC, Canby-Hagino E, Thompson IM. Testosterone Replacement Therapy and Prostate cancer: A Word of Caution. Current Urology Reports 2007;8:185–89. PMID: 17459266.

Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone Therapy in Men with Untreated Prostate Cancer. Journal of Urology 2011;185:1256–60. PMID: 21334649.

Salonia A, Gallina A, Briganti A, et al. Preoperative Hypogonadism is Not an Independent Predictor of High-Risk Disease in Patients Undergoing Radical Prostatectomy. Cancer 2011;117:3953–62. PMID: 21365624.

Risk factors

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 97% of cases occur in men over age 50.

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, in some men testosterone may stimulate the growth of prostate 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.

Eating too much, especially unhealthy foods, can lead to weight gain — and obesity seems to increase risk of developing aggressive prostate cancer (as well as other types of cancer). Although it's not clear why obesity might contribute to prostate cancer, one theory involves insulin, the hormone that enables cells in the body to utilize energy from glucose and fatty acids in the blood. Excess weight causes people to develop insulin resistance, a condition in which cells in the body become less sensitive to the effects of insulin. Over time, their bodies produce higher and higher levels of insulin so that they can derive energy from food. But insulin is also a growth factor that may behave somewhat like a chemical fertilizer. As insulin levels rise, this hormone may directly drive the out-of-control cell growth in cancer or might do so indirectly through the action of related chemicals known as insulin-like growth factors.

Although researchers do not yet know all the steps involved, there are plenty of clues that both diet and weight affect prostate cancer. That's why experts generally recommend a healthy diet high in fruits and vegetables and low in saturated fat.

Other factors. 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?").

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.

Can prostate cancer be prevented?

Knowing what increases a man's risk for prostate cancer is not the same as knowing what causes prostate cancer, or how to prevent it. The biology of prostate cancer development is incredibly complex.

For this reason, any realistic advice about prevention has to be offered cautiously, and with many caveats. It also has to be calibrated to two different groups of men: those who want to reduce their risk of developing prostate cancer in the first place (known medically as primary prevention), and those who have already undergone treatment for prostate cancer and want to reduce the chances of a recurrence (known as secondary prevention). This section discusses news about primary prevention of prostate cancer. For information about secondary prevention, see Chapter 7.

A setback for chemoprevention

In June 2011, the FDA issued a drug safety communication warning that a group of drugs once thought capable of preventing prostate cancer might actually increase a man's chance of developing the most aggressive kind. This was a stunning setback to researchers who believed in the potential of "chemoprevention" — the use of drugs to prevent prostate cancer.

The drugs the FDA warned against were both 5-alpha-reductase inhibitors — medications that are commonly used to treat benign prostatic hyperplasia (BPH). This drug class includes finasteride (Proscar, generic), dutasteride (Avodart), and the combination pill dutasteride/tamsulosin (Jalyn). Finasteride is also prescribed at a lower dose, as Propecia, to treat baldness.

Researchers initially thought these drugs had potential for prostate cancer prevention because they tamp down an enzyme called 5-alpha-reductase type 2, which the body uses to convert testosterone into a more potent hormone, dihydrotestosterone (DHT). DHT not only promotes the growth of normal prostate tissue but also fuels abnormal tumors. The logic behind testing the 5-alpha-reductase inhibitors was that by using these drugs to reduce production of DHT, it might be possible to prevent prostate cancer.

Two studies tested this hypothesis. The Prostate Cancer Prevention Trial (PCPT) followed 18,882 healthy American men, ages 55 and older, with PSA levels of 3 ng/ml or less (a range considered normal) and normal findings on the digital rectal exam (DRE). Participants were randomly assigned to take either 5 milligrams (mg) of finasteride or a placebo daily for seven years. The international Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study enrolled more than 8,000 men ages 50 to 75 considered at increased risk for prostate cancer. They had elevated PSA levels (2.5 to 10 ng/ml) but had a negative biopsy within the previous six months. Participants were randomly assigned to take 0.5 mg of dutasteride daily or a placebo daily for four years.

Both studies concluded that the 5-alpha-reductase inhibitors 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.

At first, the researchers and the drugs' manufacturers tried to demonstrate that the drugs didn't actually cause more aggressive tumors. Rather, they argued that because both drugs shrink the prostate, the biopsy needle was more likely to strike cancerous tissue if it was there. In other words, they argued that the drugs weren't causing the cancers but making them easier to find.

Ultimately, however, the FDA decided on the basis of a detailed and rigorous analysis that the facts didn't support this conclusion. During its review, the FDA asked that an independent pathologist reassess the biopsy specimens collected during the two studies and reassign Gleason scores (to determine the aggressiveness of any cancer found in the specimens). Consistent with the data already published, the pathologist found that the 5-alpha-reductase inhibitors decreased risk of low-grade cancers (Gleason score of 6 or lower). However, there was an absolute increase in the incidence of the most aggressive cancers — those with Gleason scores of 8 to 10. In the PCPT trial, 1.8% of men taking finasteride developed aggressive cancer, compared with 1.1% of those taking placebo. In the REDUCE trial, 1% of men taking dutasteride developed aggressive cancer, compared with 0.5% of men taking placebo. Put another way, for every 150 to 200 men taking these drugs for prostate cancer prevention, between three and four low-grade cancers would be prevented, but one additional high-grade cancer would occur. Based on these estimates, the FDA felt that the risks outweighed the potential benefit, leading to its decision to advise against using these drugs for prostate cancer prevention.

Although the FDA advisory generated much discussion in the research community, it probably won't have much impact on clinical practice, because few doctors were prescribing these drugs for prostate cancer prevention. One survey found, for example, that 64% of urologists and 80% of primary care physicians never prescribed finasteride for prostate cancer prevention.

However, some men with significant risk factors may still want to consider taking these drugs. And men who are taking 5-alpha-reductase inhibitors for BPH should monitor their PSA levels closely. If PSA levels start to rise in a man who is taking one of these drugs, he should talk to his doctor about possibly having a biopsy to understand what may be causing the increase, because it could be prostate cancer. For the latest research on this topic, see "5-alpha-reductase inhibitors and chemoprevention." For further discussion, see "Physician interview: Keeping the FDA ruling on 5-alpha-reductase inhibitors in perspective."

5-alpha-reductase inhibitors and chemoprevention

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.

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.

Rosenberg MT, Froehner M, Albala D, et al. Biology and Natural History of Prostate Cancer and the Role of Chemoprevention. International Journal of Clinical Practice 2010;64:1746–53. PMID: 21070525.

Theoret MR, Ning YM, Zhang JJ, et al. The Risks and Benefits of 5-Alpha-Reductase Inhibitors for Prostate-Cancer Prevention. New England Journal of Medicine 2011;365:97–99. PMID: 21675880.

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.

Vitamin E supplements may increase risk

A second setback to prostate cancer prevention efforts occurred in October 2011, when a major study concluded not only that vitamin E supplements failed to prevent prostate cancer — as once had been hoped — but actually increased risk of developing it (see "An update about Vitamin E").

An update about vitamin E

Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the Risk of Prostate Cancer: The Selenium and Vitamin E Cancer Prevention Trial. Journal of the American Medical Association 2011;306:1549–56. PMID: 21990298.

Based on earlier data, researchers had high hopes for selenium and vitamin E as cancer fighters. One study of selenium and skin cancer found that although the supplement offered no protection against skin cancer, it appeared to reduce the risk of prostate cancer. Another study of vitamin E in male smokers — designed to look at the impact of this vitamin on lung cancer — found that it reduced risk of prostate cancer. So researchers launched SELECT (Selenium and Vitamin E Cancer Prevention Trial), the largest prostate cancer prevention study ever undertaken. The study followed more than 35,000 men ages 50 and older who were randomly assigned to take one of these combinations daily:

  • 200 micrograms (mcg) of selenium and 400 international units (IU) of vitamin E

  • 200 mcg of selenium and a placebo

  • 400 IU of vitamin E and a placebo

  • two placebos.

The placebos looked exactly like the supplements. Neither the participants nor the researchers knew who received which combination. The trial was discontinued in 2008 when the independent Data and Safety Monitoring Committee reviewed five years' worth of data and discovered that the supplements, taken alone or together, didn't prevent prostate cancer.

At the 10-year mark, however, the findings were even more disturbing. By that point, men who were taking the vitamin E supplements were 17% more likely to have developed prostate cancer than those taking placebo. Although this relative risk was small, it was statistically significant — meaning it was not a fluke. In absolute terms, 529 men taking placebo developed prostate cancer during follow-up, compared with 620 taking vitamin E supplements. (Rates of both low-grade and high-grade cancers increased, although high-grade cancers remained uncommon.) In addition, the study found no reduction in prostate cancer risk in the men who took selenium supplements alone or in combination with vitamin E.

At this point, therefore, it's clear that neither vitamin E nor selenium supplements reduces the risk of prostate cancer.

Physician interview: Keeping the FDA ruling on 5-alpha-reductase inhibitors in perspective

Dr Marc B. Garnick editor in chief of this report, served as a voting member of the FDA panel that reviewed data on finasteride (Proscar, Propecia) and dutasteride (Avodart) before deciding to warn against using these drugs for prostate cancer prevention (see "A setback for chemoprevention"). He agrees with the FDA decision and provides perspective about what the recent advisory means for men.

Does this mean that chemoprevention for prostate cancer is over for now?

Essentially, yes. Some researchers may try to publish new manuscripts taking issue with the FDA advisory, but I doubt anything will come of it. The FDA analysis was thorough and based on valid interpretation of the data.

Are there any men who still might benefit from taking these drugs for cancer prevention?

Men who are at increased risk for prostate cancer because a close family member, such as a father or brother, had the disease might want to consider taking a 5-alpha-reductase inhibitor. There's ample evidence that these drugs reduce the risk of low-grade cancers by about 25%. But they have to weigh this benefit against the small but real risk that they may develop an aggressive form of cancer while trying to prevent a slow-growing one.

How would you advise men who are taking a 5-alpha-reductase inhibitor to treat benign prostatic hyperplasia (BPH)? Should they stop taking these drugs to avoid developing prostate cancer?

That's a decision only an individual can make, but it's not a simple one. The 5-alpha-reductase inhibitors are very effective at treating BPH. They decrease the possibility of developing acute urinary retention and help men to avoid more invasive surgical procedures. In my opinion, the robust benefits for using a 5-alpha-reductase inhibitor to treat BPH outweigh the small risk of developing an aggressive prostate cancer.

At the same time, a man taking one of these drugs to treat BPH also has to monitor his PSA. The 5-alpha-reductase inhibitors should reduce PSA levels by at least 50% after a man starts taking these drugs. If the PSA does not go down by that amount, I would recommend a prostate biopsy to determine whether the man already has prostate cancer.

It's also important to track PSA periodically while continuing with a 5-alpha-reductase inhibitor. Usually, physicians will take a baseline PSA at the start of treatment, then do a follow-up PSA test six months later and periodically thereafter. At that point, the PSA value should be doubled to obtain a clear comparison with PSA values in untreated men. If a man's PSA starts to rise — and especially if it more than doubles — then it's important to have a biopsy to understand what may be causing that increase.

What about men taking Propecia for baldness? Should they be worried?

There is not a lot of data about Propecia, which is a low-dose form of finasteride. When used for BPH, finasteride is prescribed at 5 mg; when it is used for baldness, it is prescribed at 1 mg. The Prostate Cancer Prevention Trial, which evaluated finasteride for prostate cancer prevention, only studied the 5-mg dose. So we don't know if the lower dose would have the same prostate cancer risks as the higher dose.

Diet and prostate cancer

"What can I eat to reduce my risk of developing prostate cancer?" This is one of the most common questions physicians hear from men concerned about prostate health. Undoubtedly, many hope that their doctor will rattle off a list of foods guaranteed to shield them from disease. Although some foods have been linked with reduced risk of prostate cancer, proof that they really work is lacking, at least for now. And sometimes additional research on a particular food only ends up causing more confusion.

For example, some studies suggest that a diet rich in fruits and vegetables may reduce risk of prostate cancer. Carotenoids, which occur naturally in plants, have antioxidant properties. Antioxidants protect cells in your body from damage by free radicals, unstable molecules produced as a natural byproduct of digestion or by exposure to environmental toxins like tobacco smoke. 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.

In 1995, a large epidemiologic study 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 review found only "very limited" evidence of a link between tomato consumption and reduced risk of prostate cancer.

Food and prostate cancer

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.

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.

The latest surprise in dietary research concerns fish. In 2003 and 2006, 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. It's not clear why fish may be protective, but one theory was that the omega-3 fatty acids in fatty fish like salmon might inhibit a particular molecular pathway involved in prostate cancer development.

Then things got complicated. First, a 2008 paper reported that eating fish was unrelated to prostate cancer incidence. But the biggest surprise came in 2011, when an epidemiologic study suggested that a particular type of omega-3 fatty acid, known as DHA, appeared to be associated with a steeply increased risk for developing aggressive prostate cancer (see "An update about fish and prostate cancer risk").

What's going on? All of this contradictory research serves as a reminder that, instead of focusing on specific foods, it's better to cultivate an overall pattern of healthy eating. This sort of "big picture" advice is the best way to ensure that you are eating a diet that improves your overall health. Focusing on a particular food, on the other hand, is an all-or-nothing approach that is usually not the best dietary strategy. Food is not medicine that you either "take" or "don't take" in carefully prescribed amounts. What you consume at any particular meal is part of an overall lifestyle that, in the aggregate, affects disease risk.

Healthy eating is easier than you might think. In a nutshell, here's what experts recommend:

  • Eat at least five servings of fruits and vegetables every day. Go for those with deep, bright color.

  • Choose whole-grain bread instead of white bread, and choose whole-grain pasta and cereals.

  • Limit your consumption of red meat, including beef, pork, lamb, and goat, and processed meats, such as bologna and hot dogs. Fish, skinless poultry, beans, and eggs are healthier sources of protein.

  • Choose healthful fats, such as olive oil, nuts (almonds, walnuts, pecans), and avocados. Limit saturated fats from dairy and other animal products. Avoid partially hydrogenated fats (trans fats), which are in many fast foods and packaged foods.

  • Avoid sugar-sweetened drinks, such as sodas and many fruit juices. Eat sweets as an occasional treat.

  • Cut down on salt. Choose foods low in sodium by reading and comparing food labels. Limit the use of canned, processed, and frozen foods.

  • Watch portion sizes. Eat slowly, and stop eating when you are full.

An update about fish and prostate cancer risk

One of the most consistent pieces of dietary advice involves the healthy fats found in fish, particularly cold-water fish such as salmon and mackerel. These fish contain high levels of two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A convincing body of evidence shows that EPA and DHA reduce risk of heart attacks and strokes — which is why the American Heart Association recommends that adults eat two servings of omega 3–rich fish a week. EPA and DHA also calm inflammation, which contributes to the development and progression of prostate cancer. That's why prostate cancer researchers were interested in learning whether these fatty acids might help prevent prostate cancer.

But an analysis of health information and blood samples collected from men during the Prostate Cancer Prevention Trial (PCPT) yielded data so surprising that even the researchers who did the study called the findings "disconcerting." Researchers who analyzed a subgroup of PCPT participants found that men with the highest levels of DHA were 2.5 times more likely to develop aggressive, high-grade prostate cancer over a seven-year period compared with men who had the lowest levels of DHA. In another surprise, men with the highest blood levels of trans fats — the unhealthy type found in processed foods — were roughly half as likely to develop aggressive, high-grade cancer in the same period as were men with the lowest levels of trans fats. These findings were exactly the opposite of what the researchers expected. So what exactly is going on?

It's not clear. The researchers speculate that because the PCPT did not require men to undergo prostate biopsies before enrolling in the study, some of the participants might already have had high-grade cancer before they entered the trial.

It's also important to put the results in perspective. The researchers analyzed blood samples from the 1,658 men who developed prostate cancer during the PCPT study. Only 125 men — about 8% of the total — developed high-grade tumors, while the vast majority, 1,533 men, developed low-grade cancer. So while high levels of DHA may increase risk of developing high-grade cancer, the risk still remains low in absolute terms.

Another thing to keep in mind is that many more men die of heart disease than from prostate cancer. Eating fatty fish prepared healthfully (poached, broiled, or grilled) in place of red meat is a good way to protect your heart, partly because substituting fish for red meat reduces levels of unhealthy LDL cholesterol in your blood. And a study released in July 2011 suggests that lower LDL cholesterol levels are associated with a decreased risk for prostate cancer.

Nutritional experts therefore agree that this one study — especially because it flies in the face of accepted wisdom — is not cause for swearing off fish. At the same time, there is as yet no evidence proving that fish prevents prostate cancer. If you eat fish, do it for your heart and your overall health. Additional studies will clarify whether there are any other benefits — or risks — to be aware of in terms of prostate cancer.

Sources: Brasky TM, Till C, White E, et al. Serum Phospholipid Fatty Acids and Prostate Cancer risk: Results from the Prostate Cancer Prevention Trial. American Journal of Epidemiology 2011;173:1429–39. PMID: 21518693.

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.

Kok DE, van Roermund JG, Aben KK, et al. Blood lipid levels and prostate cancer risk; a cohort study. Prostate Cancer and Prostatic Diseases 2011; Electronic publication ahead of print. PMID: 21727905.

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

Tests for prostate cancer

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 DRE and a PSA test (see Chapter 1). They argued that these screening techniques offered the best hope for discovering and treating cancer early, before it spread to other parts of the body. That approach wasn't perfect, but many experts believed it saved lives.

Late in 2011, however, PSA screening came under fire. In October 2011, the U.S. Preventive Services Task Force — the government's most authoritative source on screening recommendations — for the first time advised against routine PSA tests for healthy men. A day later, the American Urological Association (AUA) — the professional organization of physicians who diagnose and treat prostate cancer — weighed in. It issued a statement criticizing the new recommendations by the USPSTF.

Small wonder that many men were confused. What was lost in the ensuing (and sometimes heated) debate was that the USPSTF recommendation was really not all that radical. It was more evolutionary than revolutionary. A series of studies have raised concerns that PSA tests do more harm than good. Today most organizations recommend against regular screening (see "Consensus builds against routine PSA screening").

Ultimately, though, a recommendation is only that. You'll need to decide for yourself, with your doctor's guidance, whether to have a PSA test, but the following sections review the salient points to keep in mind.

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.

PSA — still useful in some cases

Much of the debate about PSA 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 some experts believe that a lower reading might be a more accurate cutoff point to help distinguish men with or without prostate cancer. 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 also 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 researchers think that it should 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.

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 for 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 progresses. 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.

For all these reasons, 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. However, not all cancers cause these changes. In addition, standards for evaluating PSA velocity are not yet established.

Prostate biopsy

If your doctor suspects prostate cancer on the basis of an elevated PSA level or abnormal DRE, the next step in diagnosis involves 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?") and lower PSA levels. In some situations, however, doctors use them to help assign a stage to the cancer.

*Editor's note: A bone scan detects cancer metastases. It differs from a bone density test, which is used to assess bone structure and diagnose osteoporosis.

Determining the cancer's stage

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 10). 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 substantially lower.

Figure 10: Stages of prostate cancer

Stage T1

image

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

image

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

image

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

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

image

Stages N and M

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 and potential to spread (metastasize).

Tumors often consist of multiple types of cells (see Figure 11). 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.

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 (3+2) or 6 (3+3) 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 website, 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.

Figure 11: Gleason patterns

image

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.

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.

There are several initial 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); focal therapy; hormone therapy; immunotherapy; 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 attempt to reduce unwanted side effects, such as urinary incontinence and erectile dysfunction.

In addition, researchers are always seeking to find new ways to treat prostate cancer. The past few years have witnessed an amazing amount of progress on this front — especially in treating metastatic or advanced prostate cancer. Many new drugs are now available, among them

  • abarelix (Plenaxis) and degarelix (Firmagon), both hormone therapy drugs

  • abiraterone (Zytiga), carbazitaxel (Jevtana), and sipuleucel-T (Provenge), for castrate-resistant prostate cancer

  • denosumab (Xgeva), for bone complications of prostate cancer treatment.

Still other agents are progressing through the drug development pipeline.

But the wide variety of treatments can be confusing for patients and doctors alike. In fact, the AUA'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 man, you may want to focus on treatment options that give you the best chance to preserve sexual function.

Study suggests testosterone replacement therapy may be safe for some men in remission from prostate cancer

A review of the literature suggests, in something of a surprise, that men who have successfully completed prostate cancer treatment may consider testosterone replacement therapy — as long as there is no evidence of biochemical recurrence, defined as a PSA less than 0.2 ng/ml for men who underwent radical prostatectomy and a PSA less than 2 ng/ml in men who underwent radiation therapy. If such men decide to try testosterone replacement therapy, the authors advise at least quarterly PSA tests and DREs, followed by biopsies if necessary.

Dr. Marc Garnick, editor in chief of this report, still errs on the side of caution when it comes to testosterone. He advises his own patients to wait at least 10 years after prostate cancer treatment ends before considering testosterone replacement therapy. If PSA levels remain stable — meaning there is no evidence of biochemical recurrence — testosterone therapy might be an option at that point.

Source: Dorff TB, Vogelzang NJ. Use of Testosterone Replacement Therapy in Patients with Prostate Cancer. Current Urology Reports 2011;12:223–28. PMID: 21365235.

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 50 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. And any man who tends to worry a great deal might prefer treatment over waiting and worrying, even if his tumor is slow-growing. Treatment might also make sense for men suffering from benign prostatic hyperplasia, because removing the prostate through surgery — or reducing its size with other modalities — will not only treat the cancer but also may improve urinary symptoms.

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. Although estimates vary, roughly 16% to 40% of men diagnosed with prostate cancer have tumors that are so small and apparently slow-growing that they meet the criteria for active surveillance. This is 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 active surveillance with delayed intent to treat.

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. And in the United States in particular, diagnosis usually leads to treatment. Currently fewer than 10% of men considered eligible for active surveillance choose this strategy.

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.

Eligibility and monitoring

When is it safe to wait? There are a lot of factors to weigh and no definitive answer to this question.

The whole concept of active surveillance stemmed from a 1994 article (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 (see Table 6).

Origins of active surveillance

Epstein J, 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.

During active surveillance, it's important to undergo regular monitoring to determine if the prostate cancer has become more aggressive. At that point, it's time to consider treatment.

Monitoring recommendations also vary. At a minimum, monitoring should consist of 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.

In its 2011 updated guidelines, the National Comprehensive Cancer Network — a nonprofit consortium of 21 leading U.S. cancer centers — recommended even more stringent monitoring during active surveillance. The new guidelines recommend PSA tests every three to six months; a DRE every six to 12 months; and needle biopsies once yearly.

Table 6: Risk parameters for prostate cancer

Based on one or more of the following findings

Risk assessment

PSA level

Gleason score

Cancer stage

Low

<10 ng/ml and/or

6 or less and/or

T2a or lower

Intermediate

10–20 ng/ml and/or

7 and/or

T2b

High

>20 ng/ml and/or

8–10 and/or

T2c or higher

Source: D'Amico AV. Risk-Based Management of Prostate Cancer. New England Journal of Medicine 2011;365:169–71. PMID: 21751910.

Of course, guidelines are only that — guidelines, and not mandates. Some experts — including the editor in chief of this publication — take issue with annual prostate biopsies because these can lead to erectile dysfunction, infections, and other problems. In one study that tracked side effects and complications after a series of 5,802 biopsies, for example, 3.5% of men developed a fever, 0.4% of men had urinary retention, and 0.5% of men were hospitalized for infections or prostatitis. The PLCO trial reported that, for every 10,000 prostate biopsies, 68 complications such as infections, bleeding, and urinary difficulties occurred. And most recently a review of Medicare data found that men who underwent a prostate biopsy were twice as likely to be hospitalized in the next 30 days as men who did not have the procedure. They found that nearly 7% of men who underwent the prostate biopsy were hospitalized for problems such as infection or bleeding, compared with 3% of men in the control group. (For the studies reporting on complications, see "Beware multiple biopsies.")

That being said, it is important to undergo regular monitoring of some sort while you are on active surveillance. 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.

Beware multiple biopsies

Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality Results from a Randomized Prostate-Cancer Screening Trial. New England Journal of Medicine 2009;360:1310–19. PMID: 19297565.

Loeb S, Carter HB, Berndt SI, et al. Complications After Prostate Biopsy: Data from SEER-Medicare. Journal of Urology 2011;186:1830–34. PMID: 21944136.

Raaijmakers R, Kirkels WJ, Roobol MJ, et al. Complication Rates and Risk Factors of 5,802 Transrectal Ultrasound-Guided Sextant Biopsies of the Prostate within a Population-Based Screening Program. Urology 2002;60:826–30. PMID: 12429309.

Signs that it may be time to consider treatment

Recommendations about what events should trigger treatment vary. Some changes that might be signs that it is time to consider treatment include the following:

  • biochemical changes, such as a patient's PSA increasing beyond a set threshold

  • changes in a patient's Gleason score

  • evidence that stage has advanced, based on findings from the DRE or imaging.

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

Treatment or active surveillance? What the studies say about outcomes

Most men diagnosed with early-stage prostate cancer undergo treatment for one simple — yet profoundly human — reason: they don't want to die. But does treatment really improve a man's chances of surviving prostate cancer any more than active surveillance does?

Unfortunately, there is no definitive answer yet. In 2011, three research teams reported results of studies that compared health outcomes for men who decided to pursue active surveillance with those who underwent treatment. Two studies concluded that active surveillance did not compromise survival, while a third suggested that it might. However, the studies differed in key ways that make it difficult to compare the results.

PIVOT. One of the most eagerly awaited studies — because it is the first U.S. randomized controlled trial of surgery versus watchful waiting — was the federally funded Prostate Cancer Intervention versus Observation Trial (PIVOT). Researchers presented initial results of the PIVOT study at the 2011 annual meeting of the AUA. After an average of 10 years of follow-up, radical prostatectomy did not improve chances of surviving any more than watchful waiting.

The researchers enrolled 731 men ages 75 and younger. During follow-up, nearly half of them died — 7% because of prostate cancer. Prostate cancer surgery did not significantly improve the odds of surviving. According to the researchers, 47% of men who underwent surgery and 50% of men assigned to watchful waiting died during the study. Results were also similar when they looked at deaths from prostate cancer: during the study, 6% of men who underwent surgery died of prostate cancer, compared with 8% of men assigned to watchful waiting.

Several caveats are worth noting, however. First, the findings have not yet been subjected to peer review for publication in a medical journal, and such reviews sometimes identify problems with the data. Second, the study enrolled fewer than the 2,000 men originally planned, so some researchers have questioned whether it was large enough to provide definitive conclusions.

SPCG-4 study. In contrast to the PIVOT study, another closely watched study, the Scandinavian Prostate Cancer Group Study 4 (SPCG-4), concluded that surgery does improve men's odds of surviving. SPCG-4 enrolled 695 men in Sweden, Finland, and Iceland who were randomly assigned to radical prostatectomy or watchful waiting. After 15 years of follow-up, 55 men assigned to surgery (15% of the total) died from prostate cancer, compared with 81 men in the watchful waiting group (21% of the total).

Once again, however, it's important to note some caveats. The men recruited to the SPCG-4 study were diagnosed not on the basis of a PSA test (as is common in the United States) but because of symptoms such as pain or difficulty urinating. This means that their cancers could have been more advanced than those detected through PSA screening. In addition, the watchful waiting arm did not involve the type of monitoring now recommended for men undergoing active surveillance.

Observational study. Researchers published the results of an observational study that followed 769 American men who had chosen active surveillance on their own. While not as rigorous as a randomized controlled trial, the study is nevertheless interesting because it included the more rigorous monitoring that occurs during active surveillance.

Many men were able to forgo treatment for years, and some were able to avoid it completely. At the two-year mark, 81% remained on active surveillance; at five years, 59% remained, and at 10 years, 41% remained. Moreover, none of the men died from prostate cancer during follow-up — suggesting that active surveillance was safe as long as treatment commenced once any sign of disease progression appeared.

One caveat to note here is that the researchers used the NCCN criteria for "very low risk" of prostate cancer progression. As such, the results may not apply to men at low or intermediate risk (see Table 6).

Other studies. Because active surveillance is still a relatively new option, these short-term outcomes are interesting, but they don't help men who expect to live another 15 or 20 years and want to understand whether active surveillance affects their chances of survival. Definitive guidance can only come from long-term randomized controlled studies.

In the United Kingdom, the Prostate Testing for Cancer and Treatment (ProtecT) study randomly assigned over 1,500 men either to surgery, external beam radiation, or active surveillance. The ProtecT study ended in 2008, but the researchers are now collecting data on outcomes. Unfortunately, a U.S. study, Surveillance Therapy Against Radical Treatment (START), was unable to recruit enough participants and has been stopped.

Sources: Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer. New England Journal of Medicine 2011;364:1708–17. PMID: 21542742.

Cooperberg MR, Carroll PR, Klotz L. Active Surveillance for Prostate Cancer: Progress and Promise. Journal of Clinical Oncology 2011;29:3669–76. PMID: 21825257.

Tosoian JJ, Trock BJ, Landis P, et al. Active Surveillance Program for Prostate Cancer: An Update of the Johns Hopkins Experience. Journal of Clinical Oncology 2011;29:2185–90. PMID: 21464416.

Surgery

Radical prostatectomy has always been the gold standard for the surgical treatment of prostate cancer. 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.

In the past decade, however, the way this surgery is performed has undergone a profound shift. The traditional "open" surgical technique — in which a surgeon makes a long incision in the abdomen to reach the prostate — has now been supplanted by robotic surgery, a computer-guided laparoscopic technique. In 2004, robotic surgery accounted for 15% of all prostatectomies. By 2008, it accounted for 80% of such surgeries.

Even more startling was the fact that while the incidence of prostate cancer decreased slightly between 1997 and 2008, the number of men undergoing surgery for prostate cancer actually increased. The spike was most noticeable between 2005 and 2008 — at a time when marketing of robotic surgery also increased and hospitals began promoting it. During that period, the number of prostatectomies performed grew nearly 50%, from 60,000 a year to nearly 88,000.

Although experts are divided about whether the shift to robotic surgery is a good thing, it is clear that "the robot" has transformed prostatectomy — and is probably here to stay. So far the studies suggest, however, that there is no clear "surgical winner" in terms of overall benefits and risks. While robot-assisted surgery causes less blood loss than other types of prostate surgery, there is no evidence yet that any particular technique is better than the rest in ensuring cancer control and functional outcomes (such as ability to have an erection or urinate normally). Instead, the most important determinant of surgical outcome is the experience and skill of the surgeon — not the technique used. (To learn more about what two experts think about robotic prostatectomy and other surgical options for prostate cancer, see "The rise of the robot.")

Who is eligible. 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. Both open and robot-assisted prostatectomy are technically difficult procedures, 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.

Surgical options. In the traditional method, known as the open retropubic technique, the surgeon removes the prostate and lymph nodes through an incision in the abdomen. In the laparoscopic method, the surgeon removes the prostate and lymph nodes through several keyhole incisions in the abdomen. But today, the most common type of surgery for prostate cancer is a variation of the laparoscopic method called robot-assisted prostatectomy (see Figure 12). With this technique, the surgeon sits at a console and remotely controls instruments placed through several keyhole incisions.

Figure 12: Operating robotically

image

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.

Another option, though one seldom used, is the perineal technique, in which the surgeon works through an incision in the perineum, the area between the scrotum and the anus. Proponents of this method argue 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 usually 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. However, some surgeons advocate going ahead with the prostatectomy anyway. For that reason, it's important to have this conversation ahead of time with your surgeon, so that you can express your preference about whether to go forward with the prostatectomy.

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.

Performing a prostatectomy requires a delicate balancing act. The surgeon aims to cut out the gland and enough surrounding tissue to completely remove the cancer, yet leave enough of the nerves and surrounding tissue intact to preserve erectile and urinary function. To the naked eye, it can look as if all of the cancer has been removed, but when a pathologist examines tissue samples, cancer cells may be lurking right along the edge of the cut tissue. This means that some cancer cells may have been left behind, in what doctors and pathologists term a positive surgical margin. When pathologists find a positive margin, further treatment is generally needed to remove the remaining cancerous tissue.

Although preserving erectile function is usually the foremost consideration for patients (and surgeons), it's also wise to be aware of the impact of prostatectomy on urinary function. Apical disease — meaning that the tumor is located in the apex or bottom section of the prostate, in the area surrounding the urethra — poses a particular challenge for surgeons. If they attempt to avoid damaging the urinary tract and sphincter, they may leave behind a positive margin. If they aggressively remove tissue, they may damage the sphincter and increase the risk of urinary incontinence.

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 13). This type of operation may also reduce the likelihood of other serious side effects, such as urinary incontinence and significant blood loss.

Figure 13: The prostate and its nerves

image

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 0% to 80%. Why the enormous spread? It's at least partly because some research relies on patient-reported outcomes, while other research relies on physician estimates. Not surprisingly, patients are more likely to report these problems than physicians.

It's important to choose an experienced surgeon. The likelihood of a successful outcome — in terms of preserving potency, preventing incontinence, and, most importantly, curing the cancer — generally correlates with experience. The number of procedures a surgeon performs does not necessarily make him or her 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 Chapter 5).

Efficacy. Traditional open surgery and robotic surgery are about equally effective at eradicating prostate cancer. For example, follow-up PSA tests used to determine whether PSA rises after surgery (a sign that some cancer remains and has started to grow) find that "biochemical disease-free survival" at both the five- and seven-year mark is about the same for patients who underwent open or robotic surgery.

Safety. No matter how it is performed, prostatectomy is a relatively 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.

The techniques do vary in terms of how much blood a patient may lose during surgery and whether he will require a transfusion. One review found that 20% of men who underwent open prostatectomy required a blood transfusion during surgery, compared with 3.5% of men who underwent laparoscopic surgery, and 1.4% of men who had robot-assisted surgery. But the rate of other medical complications appears similar regardless of the type of surgery. In both the review just mentioned and in a separate study, about 10% of men experienced a complication due to prostatectomy (such as respiratory distress, intestinal obstruction, urinary tract infection, or stomach pain).

Keeping statistics in perspective

The research on outcomes after surgery, radiation, and other types of prostate cancer treatments has focused mainly on men diagnosed on the basis of symptoms. There is still no proof that any of these interventions prevent death or even extend lives in men whose prostate cancers were diagnosed on the basis of screening with PSA tests.

Recovery. Depending on the technique used and a man's health, recovery usually involves one 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.

Complications. Urinary incontinence and erectile dysfunction are the most common — and often most distressing — complications of prostatectomy. A review of the literature conducted for the U.S. Preventive Services Task Force found that prostate cancer surgery significantly increased a man's chances of developing urinary incontinence. The sole randomized controlled study included in the review found that 49% of men who had prostatectomy developed urinary incontinence, compared with 21% of those who engaged in watchful waiting. In four observational studies (which followed men who had chosen one treatment or another over time), 12% to 44% of men who underwent prostate cancer surgery developed incontinence, compared with 3% to 10% of men engaged in watchful waiting.

Prostatectomy also increased a man's risk of developing erectile dysfunction. In the randomized controlled study just mentioned, 81% of men who underwent prostatectomy had problems with erections, compared with 45% of men assigned to watchful waiting. In five observational studies, 55% to 90% of men who underwent prostatectomy had erectile dysfunction, compared with 26% to 68% of the men who chose watchful waiting. (To read any of the studies in this section for yourself, see "Outcomes of prostate cancer surgery.")

Roundtable discussion: The rise of the robot

Two Harvard experts discuss how robotic prostatectomy compares with traditional open prostatectomy.

One of the most significant trends in prostate cancer treatment in recent years has been the shift away from traditional "open" surgery toward robotic prostatectomy, a variation on laparoscopic surgery. Today about 80% of men with prostate cancer who choose surgery undergo a robotic prostatectomy. But is this always the wisest choice? And what factors should a man take into consideration when talking with his urologist about the best treatment?

In technical terms, the two types of surgeries involve entirely different approaches. During an open prostatectomy, the surgeon makes an incision that starts below the belly button and goes down to the pubic bone. To reach the prostate, the surgeon has both hands in the patient's abdomen and is able to palpate (examine) the bladder and the prostate, as well as peel nerves away from the prostate, when that is possible. He also manually sutures the wound closed and reconnects the bladder to the urethra.

During robotic surgery, the surgeon makes five or six half-inch incisions in the patient's abdomen. The surgeon then inserts an optic camera through the belly button and long, thin instruments through the other incisions. This is similar to the procedure used in laparoscopic surgery, except that in robotic surgery, the surgeon has a three-dimensional view and controls the instruments mechanically with the use of imaging and a computer system.

In terms of outcomes, however, the two surgical approaches seem comparable — at least according to the few studies comparing them (see "Outcomes of prostate cancer surgery"). But all research has limits, and much of real-world clinical practice is never captured by studies. For that reason, the editors of Harvard Medical School's 2012 Annual Report on Prostate Diseases invited two distinguished Harvard surgeons to participate in a roundtable discussion on the topic:

  • Kevin R. Loughlin, M.D., M.B.A., is a professor of surgery (urology) at Harvard Medical School and a senior surgeon and director of urologic research at Brigham and Women's Hospital. He is also a staff urologist at Harvard University Health Services.

  • Andrew A. Wagner, M.D., is the director of Minimally Invasive Urologic Surgery at Beth Israel Deaconess Medical Center. He is an expert in the field of minimally invasive surgery for prostate cancer, including robot-assisted laparoscopic radical prostatectomy.

Dr. Marc B. Garnick, editor in chief of the 2012 Annual Report on Prostate Diseases, moderated the session.

What do you see as a key difference between robotic prostatectomy and open prostatectomy?

WAGNER: In robotic surgery, the surgeon is seeing the patient's anatomy magnified through the telescope. In the case of robotics, it's a bifocal lens, which means there are actually two lenses inside one camera, giving you a three-dimensional view of the pelvic anatomy, and it's very magnified and visible in high definition. So, the visualization is improved with robotic surgery.

LOUGHLIN: There's not a huge difference between open prostatectomy and robotic surgery. I think many people believe that robotic surgery is more precise and less likely to cause physician fatigue, because the surgeon is seated at a control panel. With open prostatectomy, the surgeon is standing at the operating table, doing the surgery. So it could be more fatiguing.

How do operative times compare?

WAGNER: Depending on the surgeon's experience, the operation lasts between two and four hours for both open and robotic.

How long a hospital stay should a man expect for an open surgery? For robotic?

LOUGHLIN: For open prostatectomy, the hospital stay usually lasts two days. After robotic surgery, it might be a one-day stay.

WAGNER: It's typically a one- or two-night stay after robotic surgery. The hospital stay after open surgery can either be the same or a day or two longer.

Any difference in terms of how long the catheter is in place?

LOUGHLIN: There is no difference between the two in the amount of time the catheter stays in. Usually the catheter comes out in 10 days, depending on the patient's situation and the surgeon's preference.

WAGNER: It's one to two weeks for the catheter, for both open and robotic prostatectomy.

So far the research suggests that patient outcomes are about the same, but one study found that robotic prostatectomy might cause more urinary incontinence and erectile dysfunction. What do you think?

LOUGHLIN: In experienced hands, there do not seem to be any differences in terms of complications such as erectile dysfunction or incontinence, or in positive margin rates.* So it basically comes down to what the surgeon trained in and what he or she is comfortable doing. But results are the same for the patient. Most people are able to resume their normal activities in a few weeks, no matter what surgery they chose.

WAGNER: One paper reported that robotic surgery caused more erectile dysfunction and incontinence. But if you read that paper critically, they were looking at patients treated from 2003 to 2007, and the vast majority of those patients were treated over the first three years, between 2003 and 2005. The first robotic prostatectomy was done in about 2000. So, right off the bat, you know that this is a relatively early snapshot of outcomes after robotics. Most of the patients from this study were in the very relatively early phase of the surgical learning curve and there were other deficiencies in the way the data were analyzed, making definitive conclusions difficult.

What's the alternative?

WAGNER: Another study, the Pros QA2 study, is a good example of how to collect patient data. It's a multi-institutional study looking at comparative effectiveness of open versus robotic prostatectomy where patients actually report how they're doing using a validated survey, not using doctor's coding forms, which are notoriously inaccurate.

Are there any other complications that men should think about?

WAGNER: I think one of the things that people don't talk about a lot is the stricture of the bladder neck or urethral stricture rate.* When you're doing robotic surgery, you actually see the bladder tissue meet the urethral tissue when you're sewing it together. If you know there's a true tissue connection between bladder and urethra, then you don't need to leave the catheter in for very long and scar tissue (or stricture) is rare. Some experienced open surgeons have reported stricture rates of about 10%. Even relatively inexperienced robotic surgeons have a much lower stricture rate of about 1% to 2%.

What's the worst complication of surgery you've ever heard about — and whattype of surgery caused it?

LOUGHLIN: I heard a case presented at another hospital, where a surgeon who was inexperienced at robotic surgery ended up cutting both of a patient's ureters during the surgery.* At that point, they had to convert to open surgery and repair the damage.

WAGNER: One of our patients developed bleeding in the pelvis that pushed his bladder aside and caused one of the bladder sutures to come loose. He developed a postoperative urinary leak as a result. We discharged him after about five days in the hospital, but he continued to leak for almost six weeks. We finally decided to admit him to the hospital and continue to drain his catheter until it healed itself. Currently he is doing well, however, with full urinary control. He also recovered erectile function.

Roughly how many robotic surgeries have to convert to open surgeries?

LOUGHLIN: There's a very small conversion rate. It's not an issue.

WAGNER: I agree. I think that the rate of conversion from robotic to open is less than 1%.

What are some of the reasons for conversion?

WAGNER: Catastrophic bleeding from a complication, such as an injury to a major artery, like an iliac artery. That might occur during a lymph node dissection.

Another reason is anesthetic complication due to the positioning. During robotic surgery, patients have to be in a steep head-down, feet-up position. So, if the patient is extremely obese and his heart or lungs can't tolerate that position, then you would have to take him out of that position and potentially convert. Many obese patients tolerate that position well, but it's something I think about and counsel patients that a conversion may be necessary.

Why do you have to put them in the extreme head-down position?

WAGNER: Because we have to have a clear view of their pelvis, which means we have to get their intestines out of the pelvis. If they put their head down, the intestines fall back into the upper abdomen. During open surgery, the surgeon is able to just push the intestines away, but in robotic surgery you need help from gravity.

The best outcomes are achieved in high-volume centers, with experienced surgeons. How many cases does a surgeon have to perform before becoming proficient at open or robotic prostatectomy?

LOUGHLIN: Generally speaking, I think a surgeon needs to do 100 of any type of procedure before becoming truly proficient at it. But I also think it's important for patients to consider more than just the experience of a surgeon. You want an experienced team, including an anesthesiologist who's done a lot of cases, and experienced nurses. So it's a whole team.

WAGNER: I think there are two types of learning curves. One involves safety, which means the surgeon can get through an operation in a reasonable amount of time so there are no anesthetic complications. If a surgeon is already an expert at doing open prostatectomies and he has some exposure to laparoscopy, he'd probably have to do about 30 robotic cases to reach the point where he could do the procedure safely. And depending on the number of cases he performs a month, that could take either a month or three years. Some others have suggested that several hundred cases have to be performed before proficiency can be achieved.

Now, the learning curve for doing a very high-level prostatectomy, where the patients have excellent cancer outcomes and excellent functional outcomes, is probably at least 200 cases. That's because the anatomy around the prostate is very complicated. Even if a surgeon has done hundreds of open prostatectomies, the robotic approach is a very different approach and the surgeon is coming at the anatomy from a completely different angle.

So, what happens to the patients who are treated before a surgeon completesthis learning curve?

WAGNER: They probably don't fare as well in terms of urinary and sexual function, which is why it behooves patients to find out how many of these surgeries their surgeon has performed and whether they have advanced training and how many they are performing on a regular basis. This applies to both open and robotic surgery.

I would say the world's best open surgeons have done thousands of cases and they will tell you that they're still learning, just like the world's best robotic surgeons are still learning every time they do a case. A surgeon probably needs to do anywhere from 300 to 500 cases before he is able to offer consistent results.

Critics say that once the robot's been purchased, it needs to be fed often with patients who don't need such an operation. How do you respond to that?

LOUGHLIN: In the first year after a hospital purchases a robot, the number of robotic prostatectomies does seem to go up. But it's hard to parse out if that's because the hospital is encouraging doctors to "feed the robot," or if the fact that the hospital has the device attracts patients to the hospital. So in other words, the whole volume of surgery may be increasing.

WAGNER: Many hospitals actually discourage the use of the robot because the instrumentation is very expensive and, if you look on a case-by-case basis, robotic cases have a much lower profit margin than open cases. So, it's not true that hospitals want the robot to be fed. Some hospitals are just the opposite — they discourage the use of the robot, believe it or not.

What are the costs of open prostatectomy vs. robotic — such as hospital fees, surgeon's fees, and so on? Is one significantly more expensive than the other?

LOUGHLIN: Hospitals don't make as much money on robotic surgery as they do on open prostatectomies. There's the amortization on the million-dollar machine to consider. And there is lots of disposable equipment with the robot.

Disposable instruments add to the cost. Most of the robotic instruments can be used 10 times and then need to be replaced, while open instruments can be used thousands of times. So I can use a pair of open scissors for 10 years, but the robotics scissors can only be used for 10 cases.

What about hospital costs and professional fees?

WAGNER: Fees for the hospital and surgeon are similar for both open and robotic surgery.

What do you think is the best type of surgery for men with prostate cancer to have?

LOUGHLIN: It really depends on the patient's individual circumstances. In prostate cancer, there are some black-and-white parameters, but mostly the situation consists of shades of grey. That is where you need your urologist to help you weigh all the factors and make a decision. You could have a 59-year-old man and a 79-year-old man with the same Gleason scores and PSA levels, and they might choose different surgeries.

WAGNER: It's a complicated question, and the answer really depends on the surgeon's experience and the patient's preference. Over all I believe robotic surgery is better than open surgery, for several reasons. There is less blood loss, which means you can often see the anatomy better. When you expand the inside of the abdomen using carbon dioxide, it actually pushes the blood back into the venous sinuses. So, there's not as much venous bleeding. If you look at most of the data about blood loss, the average blood loss during open prostatectomy is about one liter or 800 cc for an experienced surgeon, and the average for a robotic is about 100 cc. So it's significantly less. Moreover, the instrumentation allows for a more consistent dissection and reconnection of bladder to urethra.

Who's the best candidate for each type of surgery? If John Q. Public walks into your clinic, how do you make a recommendation on which surgery to have?

LOUGHLIN: There isn't a "best" kind of patient for any type of prostatectomy. That's why it's important to have a long discussion with your surgeon, to figure out what's best for you. That being said, I've found that really obese patients do better with robotic surgery. I think performing open prostatectomy is difficult when the patient has a lot of fat in the abdomen.

Any other thoughts?

LOUGHLIN: There is not a single recommendation for a type of surgery. Both surgical approaches can be curative. There was no difference between cure rates and side effects such as erectile dysfunction.

I advise patients to do a lot of reading on your own before seeing a doctor. Go to the doctor with a list of questions written down, so you can make sure you cover them all. It's also a good idea to bring a spouse or good friend along with you to the appointment. Four ears are better than two! And your companion may ask something that doesn't occur to you, or recall something from the visit you don't remember. Finally, it's unlikely that you will cover everything in a single office visit. Find out how to get back in touch. An open and ongoing dialogue is so important.

Outcomes of prostate cancer surgery

Agarwal PK, Sammon J, Bhandari A, et al. Safety Profile of Robot-Assisted Radical Prostatectomy: A Standardized Report of Complications in 3317 Patients. European Urology 2011;59:684–98. PMID: 21324583.

Chou R, Croswell JM, Dana T, et al. Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force. Annals of Internal Medicine 2011;Electronic publication ahead of print. PMID: 21984740.

Coelho RF, Rocco B, Patel MB, et al. Retropubic, Laparoscopic, and Robot-Assisted Radical Prostatectomy: A Critical Review of Outcomes Reported by High-Volume Centers. Journal of Endourology 2010;24:2003–15. PMID: 20942686.

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

Marberger M. Is Robot-Assisted Radical Prostatectomy Safer than Other Radical Prostatectomy Techniques? European Urology 2011;59:699–700. PMID: 21353381.

Mottrie A, De Naeyer G, Novara G, Ficarra V. Robotic Radical Prostatectomy: A Critical Analysis of the Impact on Cancer Control. Current Opinions in Urology 2011;21:179–84. PMID: 21427584.

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 hormone therapy (see "Combination hormone/radiation therapy").

Table 8: 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.

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.

Stereotactic radiation therapy (e.g., CyberKnife, Gamma Knife)

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 (a slightly different type of stereotactic radiation therapy)

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. 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.

No single form of radiation therapy has emerged as the best way to treat 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 8. (For what the studies say, see "Research on radiation therapy.")

Research on radiation therapy

Arvold ND, Chen MH, Moul JW, et al. Risk of Death from Prostate Cancer after Radical Prostatectomy or Brachytherapy in Men with Low or Intermediate Risk Disease. Journal of Urology 2011;186:91–96. PMID: 21571341.

Bannuru RR, Dvorak T, Obadan N, et al. Comparative Evaluation of Radiation Treatments for Clinically Localized Prostate Cancer: An Updated Systematic Review. Annals of Internal Medicine 2011;155:171–78. PMID: 21646550.

Boorjian SA, Karnes RJ, Viterbo R, et al. Long-Term Survival After Radical Prostatectomy Versus External-Beam Radiotherapy for Patients with High-Risk Prostate Cancer. Cancer 2011;117:2883–91. PMID: 21692049.

In addition, your doctor will likely recommend a type of radiation treatment based on the stage of your cancer, PSA levels, and tumor Gleason score. These together determine your risk profile. Although definitions of what constitutes low or high risk vary slightly depending on the study, you can make a quick and simple assessment of your risk based on those included in a recent review (see Table 6). However, the best method is to work with your clinician and use an online calculator (or nomogram) to determine your risk.

Brachytherapy is usually offered only to men with early-stage prostate cancer who are considered low risk. External beam radiation therapy combined with hormone therapy is the standard for men with more advanced cancer or an intermediate- to high-risk profile. External beam radiation is also sometimes used after surgery if tissue that has been removed reveals the cancer has spread beyond the prostate capsule (stage T3 or greater). Or it may be used some months after surgery if a PSA test indicates the presence of residual cancer.

Ask a doctor: What is bladder neck contracture?

I had a radical prostatectomy a month ago. The catheter came out after two weeks and at first I could urinate normally. But then the flow slowed to a dribble. My doctor has scheduled a cystoscopy because he thinks I may have a bladder neck contracture. What is that? Can it be treated?

A bladder neck contracture is a blockage in the urethral channel where the urethra has been sewn to the bladder after the prostate is removed. Unfortunately, a bladder neck contracture is a fairly common complication of radical prostatectomy. An analysis of Medicare claim data reported that 6% of men with prostate cancer who underwent minimally invasive surgery developed a contracture, while 14% of men who underwent open surgery did so. Other studies have reported that anywhere from 3% to 26% of men who undergo radical prostatectomy develop bladder neck contractures.

There are effective treatments, but sometimes men have to try more than one before they obtain relief.

A doctor can diagnose the problem using a cystoscope, which is a device with a thin tube attached to a small camera. During cystoscopy, the doctor inserts the tube slowly up through the urethra into the bladder and may also insert a thin instrument to dilate the urethra. In some men, this may be enough to solve the problem.

If these first approaches don't work, the next step is surgery. For smaller contractures, your doctor can remove the scar tissue during cystoscopy. More extensive contractures require other types of surgery. No matter what type of surgery is used, you may also have to perform self-catheterization to empty your bladder and give your urethra more time to heal (see Figure 6).

— William C. DeWolf, M.D.
Professor of Surgery (Urology), Harvard Medical School
Chief of the Division of Urology, Beth Israel Deaconess Medical Center

So far the evidence suggests that radiation therapy is just as effective as surgery at controlling prostate cancer — at least in men with a high-risk profile. In 2011, researchers reported that 92% of men treated with either radical prostatectomy or external beam radiation therapy, with or without androgen deprivation therapy, were still alive 10 years later.

Lessening radiation's toll

A distressing, though usually transient, side effect of any radiation therapy occurs in the bowel and rectum. Because these structures, part of the gastrointestinal tract, are located near the prostate, they can be damaged during treatment, resulting in problems such as diarrhea, blood in the stool, and rectal pain. Researchers are testing ways to reduce these problems.

In 2011, two studies found that intensity-modulated radiotherapy (IMRT) was less likely to cause gastrointestinal problems than three-dimensional conformal radiotherapy (3D-CRT), once the standard type of radiation therapy for prostate cancer. One paper found that IMRT caused only half as many gastrointestinal problems as 3D-CRT. In addition, researchers collaborating on the Radiation Therapy Oncology Group trial reported at the Annual Meeting of the American Society for Radiation Oncology that IMRT reduced such side effects by 26% when compared to 3D-CRT.

Source: Sharma NK, Li T, Chen DY, et al. Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated with Androgen Deprivation Therapy for Prostate Cancer. International Journal of Radiation Oncology, Biology, and Physics 2011;80:437–44. PMID: 21050673.

The use of radiation therapy in men at low or moderate risk is more controversial, especially in men 60 and younger (see "The age factor"). In 2011, researchers reported that brachytherapy was just as effective as radical prostatectomy for men with low- or intermediate-risk profiles. But the study followed men only for an average of four to five years, which is not long enough to provide insight into long-term survival. We may have more information in the years ahead, when a well-designed trial known as the ProtecT study, now under way, provides data comparing surgery to radiation.

The age factor

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.

The most common side effects of radiation therapy are bowel problems (such as diarrhea, blood in the stool, and rectal pain), urinary difficulties, and impotence. Some of these problems may become worse with time. Although some studies have tried to quantify the risks of such side effects, most of them have not provided details about the type of radiation or dose. One observational study that did report such details found that external beam radiation therapy was least likely to cause urinary incontinence, and that low-dose brachytherapy was least likely to cause erectile dysfunction (see Table 7). There is also a small but definite increased incidence of rectal cancer after radiation therapy. Researchers are investigating ways to reduce these side effects by modifying treatments (see "Lessening radiation's toll").

Table 7: Rates of side effects reported by patients three years after intervention

Type of radiation therapy

Percentage of men with urinary incontinence

Percentage of men with erectile dysfunction

High-dose brachytherapy

7%

72%

Low-dose brachytherapy

5.4%

36%

External beam radiation therapy

2.7%

68%

Source: Smith DP, King MT, Egger S, et al. Quality of Life Three Years After Diagnosis of Localized Prostate Cancer: Population Based Cohort Study. BMJ 2009;339:b4817. PMID: 19945997.

External beam radiation. During external beam therapy (see Figure 14), 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.

Figure 14: External beam radiation therapy

image

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.

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.

Several types of external beam radiation therapy are used:

  • Three-dimensional conformal radiation therapy (3D-CRT) was once the standard form of outpatient radiation therapy. 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 newer 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, the gland's exact location must be determined at the start of each treatment. This is now the most commonly used form of radiation therapy in the United States.

  • 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. During proton beam therapy, radiation is released in a very narrow band, thus minimizing damage to surrounding tissue. 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.

  • Stereotactic body radiation uses image guidance and computer-controlled robotics to deliver multiple beams of radiation to the tumor from almost any direction. (Several devices are available to deliver this form of radiation, so patients may also hear this method referred to as the CyberKnife, the Gamma Knife, TomoTherapy, and so on.) While planning treatment, the radiologist implants gold fiducials (tiny seeds that are different from the seeds used in brachytherapy) in the prostate gland to outline it and make it more visible during treatment. The computer system tracks the tumor's position, detects prostate movement, and automatically adjusts the delivery of radiation, if necessary, to account for any change.

  • Brachytherapy seeds. 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, sometimes called low-dose brachytherapy or seed implantation. This involves placing 50 to 150 radioactive seeds or pellets (depending on the size of the prostate gland) in or near the prostate tumor (see Figure 15).

Figure 15: Permanent brachytherapy (seed implants)

image

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 either general or 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.

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 often seeds are linked together into strands before insertion.) 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 some instances, 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 that contain the seeds 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. However, most radiation facilities do not offer high-dose-rate brachytherapy because other treatments are less complicated and usually just as effective.

Focal therapy

One of the newest innovations in prostate cancer treatment is focal therapy. Instead of removing or ablating the whole prostate, focal therapy, also called targeted therapy, treats the part of the prostate where the cancer is located. Focal therapy has been likened to a lumpectomy done for breast cancer, in which only the cancerous mass is targeted, while sparing the rest of the breast. In the same way, focal therapy destroys the tumor while sparing surrounding tissues. The hope is that this approach will not only eradicate the cancer, but also spare men distressing side effects such as erectile dysfunction and urinary incontinence.

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 use mapping biopsies to better determine whether cancer has spread to the seminal vesicles and can map a tumor's location more precisely than ever before (see Figure 16).

Figure 16: Mapping biopsies

image

During a mapping biopsy, tissue samples are taken every 5 millimeters, front to back and side to side. The radiologist places a grid over the perineum to aid the process. 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.

Focal therapy is best understood as an overall approach to treatment — one that can use several methods. It is also still experimental, with many questions remaining about the ideal patient and technique. The techniques most often used for focal therapy so far are cryotherapy (FDA-approved) and high-intensity focal ultrasound, or HIFU (still experimental).

Although focal therapy certainly seems promising, it's wise to keep some cautions in mind. One concern is that focal treatment may leave some cancer behind. Incomplete treatment or a missed spot of cancer could have profound consequences, at a minimum requiring additional treatment for a primary tumor (and possibly worsening outcome because the cancer may become more aggressive). That is why long-term studies are needed to assess whether focal therapy is truly as effective as prostatectomy or radiation. In addition, there is always 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%.) 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.

So for now focal therapy remains investigational. Only men who have low-risk, localized prostate cancer — and who are not eligible for or able to tolerate other types of prostate cancer treatments — should consider enrolling in a clinical trial of this modality. For information about studies that are under way, see www.clinicaltrials.gov.

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. In the 1990s, improvements in technology raised hopes that cryotherapy might be used to treat prostate cancer.

Although approved by the FDA and covered by Medicare, cryotherapy for localized prostate cancer isn't widely offered. And few randomized controlled studies involving cryotherapy exist. Most research consists of case series — outcomes of individual patients over time. 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.

Complications may be severe. Possible complications from cryotherapy include a rectal fistula (an abnormal opening in the skin near the anus that leads to the rectum), urinary stress incontinence, and — most often — impotence, which affects 47% to 100% of men after treatment, because there's no way to avoid freezing and destroying some nerves.

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. HIFU increases the intensity of the sound waves and focuses them on a single point, thereby sending a large amount of energy into the tissue — in this case, the prostate. The energy creates heat — temperatures can rise to 60° C (140° F) or higher — that irreversibly damages cells in seconds. The sound waves also create vibration, which disperses the energy and enhances tissue destruction.

HIFU is still considered experimental in both the United States and much of Europe. Some men seeking treatment have traveled to Mexico or Canada for the procedure. Until studies determine whether HIFU is safe and effective over longer periods of time, men should consider undergoing it only as part of a clinical trial. Several HIFU studies are now under way, with recruitment criteria and details listed at www.clinicaltrials.gov.

The most frequent complications after HIFU are urinary incontinence, other bladder and urethral conditions, and erectile dysfunction. The available research suggests that erectile dysfunction affects 20% to 77% of men who undergo HIFU — a range so broad that the studies likely used different criteria to assess erectile function or recruited different populations of men.

Others. Other methods being tested for focal therapy are still investigational themselves — and there is little published research on them. One such option is photodynamic therapy (PDT), in which 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. Still other researchers are investigating the use of lasers to deliver focal therapy.

Research on focal therapy

Bahn DK, Silverman P, Lee F, Sr., et al. Focal Prostate Cryoablation: Initial Results Show Cancer Control and Potency Preservation. Journal of Endourology 2006;20:688–92. PMID: 16999628.

Lindner U, Lawrentschuk N, Schatloff O, et al. Evolution from Active Surveillance to Focal Therapy in the Management of Prostate Cancer. Future of Oncology 2011;7:775–87. PMID: 21675840.

Nguyen CT, Jones JS. Focal Therapy in the Management of Localized Prostate Cancer. BJU International 2011;107:1362–8. PMID: 21223478.

Onik G, Vaughan D, Lotenfoe R, et al. The "Male Lumpectomy:" Focal Therapy for Prostate Cancer Using Cryoablation Results in 48 Patients with at Least 2-Year Follow-Up. Urologic Oncology 2008;26:500–05. PMID: 18774463.

Rove KO, Sullivan KF, Crawford ED. High-Intensity Focused Ultrasound: Ready for Prime Time. Urologic Clinics of North America 2010;37:27–35. PMID: 20152517.

Hormone therapy

Androgens, the family of male sex hormones that includes testosterone, function as a fuel for growth in normal development. However, in some men they can also drive the 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 17). Hormone therapy is a treatment option for men who

  • have cancer that has spread beyond the prostate (metastatic disease)

  • 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 (see "Combination hormone/radiation therapy")

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

Figure 17: How hormone therapy works

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.

Understanding the androgen cascade

image

  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.

Second-line hormone therapy

image

Abiraterone (Zytiga) reduces production of androgens in both the adrenal glands and the testicles, which normally produce male hormones. In addition, the drug targets prostate cancer cells which — in men with castrate-resistant prostate cancer — start producing their own androgens.

In the past, hormone therapy meant the surgical removal of both testicles (a major source of testosterone), 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 9).

Table 9: Hormone therapy medications

Drug name

Side effects

Comments

LHRH agonists

goserelin (Zoladex)

histrelin (Vantas)

leuprolide (Eligard, 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, diarrhea; rarely, liver failure

Taken orally. Liver function should be checked periodically.

Second-line hormone therapy

abiraterone (Zytiga)

Joint swelling or discomfort, low levels of blood potassium, fluid retention in legs and feet, increased blood pressure, muscle aches, hot flashes, and urinary and gastrointestinal problems

In combination with a low-dose steroid, abiraterone is approved to treat men whose prostate cancer no longer responds to hormone therapy or docetaxel. It can extend survival.

Hormone therapy produces the same benefits as orchiectomy, but patients must take the prescribed medications as scheduled. 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 used less often.

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. During this period, symptoms may worsen (a situation known as a "clinical flare"). For that reason, anti-androgens may be prescribed in conjunction with LHRH agonists to counteract that surge. (This strategy is 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 onto receptors on prostate cells.

Another option is to use a GnRH antagonist. Two are currently available: abarelix (Plenaxis) and degarelix (Firmagon).* These drugs 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 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.

A study published in 2011 suggests that abarelix — which works fast — might even be worth trying first. The researchers recruited 176 patients, most of whom had localized prostate cancer, although some had advanced or metastatic disease. They found that 12 weeks of abarelix treatment reduced testosterone levels to castration levels in most of the men. During the same period, PSA levels decreased from a mean of 20.5 ng/ml at the start of the study to 3.7 ng/ml after 12 weeks. Participants then took an LHRH agonist for another eight weeks. Testosterone levels and PSA remained stable during that period. The study thus suggests that using abarelix first reduces or even eliminates the usual testosterone surge caused by an LHRH agonist — and obviates the need for an anti-androgen (see "A new approach").

A new approach

Garnick MB, Mottet N. New Treatment Paradigm for Prostate Cancer: Abarelix Initiation Therapy for Immediate Testosterone Suppression Followed by a Luteinizing Hormone-Releasing Hormone Agonist. BJU International 2011;Electronic publication ahead of print. PMID: 22093775.

A new option. The FDA approved a new hormone therapy, abiraterone (Zytiga), in 2011. Abiraterone works in a different way from the taxanes. It shuts off testosterone production within prostate cancer cells (known as intracrine testosterone production). This is significant because intracrine signaling is believed to promote bone metastases in prostate cancer. By interfering with the signals, abiraterone may help slow the progression of bone metastases.

This new drug can extend survival in men who have run out of other options. One study of abiraterone, for example, found that men taking the drug lived four months longer on average than those taking placebo.

Common side effects. The drugs used in hormone therapy may cause side effects. Because the drugs interfere with testosterone, sexual function is often a casualty of hormone therapy. Most men experience impotence and a loss of sexual desire. When treatment is stopped, however, sexual function usually returns. Hot flashes are also extremely common with hormone therapy. Some patients also lose muscle mass or experience breast enlargement on these drugs. Others may have gastrointestinal upset, including diarrhea. 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.

Bone problems. Bone problems may develop in men with advanced prostate cancer — either because bone metastases have weakened bones, or because hormone therapy has reduced bone mass as a side effect of treatment. Secondary complications of bone metastases, known as "skeletal-related events," include pain, bone thinning, fractures, and spinal compression. Typically such skeletal-related events have been treated with pain medication and either radiation or surgery to stabilize bone.

In 2010, the FDA approved the drug denosumab (Xgeva) to prevent skeletal-related events in patients whose cancer had metastasized to the bone, largely on the basis of a study that found that the drug increased bone density and reduced the risk of spinal fractures by more than half in prostate cancer survivors, as well as two studies of patients with breast and other forms of cancer. In 2011, the FDA expanded the approval to include treatment of men at risk for bone fractures because they are taking hormone therapy for advanced prostate cancer. Denosumab works by blocking a substance known as a RANK ligand, which is necessary to activate cells called osteoclasts that break down bone. By blocking the RANK ligand, denosumab prevents bone erosion. (For more information, see "Data on denosumab.")

Data on denosumab

Fizazi K, Carducci M, Smith M, et al. Denosumab versus Zoledronic Acid for Treatment of Bone Metastases in Men with Castration-Resistant Prostate Cancer: A Randomised, Double-Blind Study. Lancet 2011;377:813–22. PMID: 21353695.

Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer. New England Journal of Medicine 2009;361:745–55. PMID: 19671656.

Smith MR, Saad F, Coleman R, et al. Denosumab and Bone-Metastasis-Free Survival in Men with Castration-Resistant Prostate Cancer: Results of a Phase 3 Randomised, Placebo-Controlled Trial. Lancet 2011;Electronic publication ahead of print. PMID: 22093187.

Two other drugs used to build bone mass in men with prostate cancer work in a different way. The bisphosphonates zoledronic acid (Zometa) and pamidronate disodium (Aredia) directly target osteoclasts, causing these bone-eroding cells to undergo the orderly process of cell suicide known as apoptosis — and thereby preserving bone (or at least slowing bone loss). A head-to-head trial in men with bone metastases from prostate cancer found that denosumab might prevent fractures better than zoledronic acid. On average, a fracture occurred four months later in men taking denosumab than those taking zoledronic acid (at 21 months versus 17 months).

Men taking any of these bone-preserving drugs are at risk for a rare dental complication, so you should see a dentist before taking any of them (see "Protecting your teeth").

Protecting your teeth

The bone agents used to help men with prostate cancer can cause a rare but distressing problem known as osteonecrosis of the jaw, in which the jaw bone dies after its blood supply is cut off. It is not clear who might develop this condition, although men who undergo invasive dental work — such as tooth extraction — while taking a bone agent seem to be more at risk. For that reason, it is important to see your dentist for a checkup, and consider having any tooth or jaw problems treated, before starting a bone drug. While taking bone drugs, brush your teeth and floss regularly and continue seeing your dentist for checkups.

Cardiovascular risks. Hormone therapy for prostate cancer — especially diethylstilbestrol (DES) — can increase total cholesterol and triglyceride levels, as well as blood sugar levels and risk of diabetes. All of these changes can increase a man's risk of developing cardiovascular disease. Recent research suggested that even GnRH agonists — the most common type of hormone therapy prescribed today — might increase the likelihood of having a heart attack or developing other cardiovascular problems. For example, a 2006 study found that use of hormone therapy increased risk of heart disease, heart attack, and sudden cardiac death. A 2007 study that analyzed the Cancer of the Prostate Strategic Urologic Research Endeavor (CaP-SURE) database found that hormone therapy more than doubled the risk of death from heart disease in men who had a radical prostatectomy. Another 2007 study that analyzed data from two randomized controlled trials concluded that, in men older than 65, hormone therapy accelerated the progression to having a fatal heart attack. The evidence was compelling enough to prompt the FDA in 2010 to issue a safety warning, requiring that GnRH agonists carry a safety warning about increased risk of diabetes, heart attack, sudden cardiac death, and stroke. (To read the studies warning of risk, see "Evidence of cardiovascular risk.")

Evidence of cardiovascular risk

D'Amico AV, Denham JW, Crook J, et al. Influence of Androgen Suppression Therapy for Prostate Cancer on the Frequency and Timing of Fatal Myocardial Infarctions. Journal of Clinical Oncology 2007;25:2420–25. PMID: 17557956.

Keating NL, O'Malley AJ, Smith MR. Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy for Prostate Cancer. Journal of Clinical Oncology 2006;24:4448–56. PMID: 16983113.

Tsai HK, D'Amico AV, Sadetsky N, et al. Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality. Journal of the National Cancer Institute 2007;99:1516–24. PMID: 17925537.

But studies published in 2008 and 2009 found no extra cardiac risk in men taking hormone therapy. And a review and meta-analysis published in 2011 raised further doubts. Researchers examined the results of eight randomized controlled trials, involving 4,141 men with high-risk prostate cancer, and found that those who had received hormone therapy (all involving GnRH agonists) were no more likely to die of cardiovascular disease than those who had not. Over all, 11% of men in both groups died of cardiovascular disease during follow-up. The researchers also found that hormone therapy reduced a man's risk of dying from prostate cancer and improved his overall chances of survival during follow-up.

An editorial that accompanied the study, however, pointed out several limitations to keep in mind. First, because the investigators only tracked cardiovascular deaths, the 2011 study provides no information about whether hormone therapy worsened cholesterol, increased blood pressure, or otherwise harmed the heart. Second, the analysis was restricted to a particular group of patients — men with high-risk prostate cancer that had not yet spread enough to be detected. It is therefore not clear whether the results apply to other groups of patients. Finally, although randomized controlled trials are often hailed as the gold standard of medical research, they do have limitations. Most notably they tend to exclude older patients and those with multiple health conditions — who ironically make up the bulk of "real world" patients. (To read the studies suggesting hormone therapy might not increase heart risk, see "Doubts raised about cardiac risk.")

Until more research becomes available, any man with prostate cancer who already has heart disease or is at increased risk for it because of high blood pressure, diabetes, or other factors needs to talk with his doctor about whether hormone therapy is an option. Before starting hormone therapy, ask your doctor to measure your blood sugar, blood pressure, and cholesterol levels. It may also be wise to consider an exercise stress test to determine your overall heart health. Then monitor your risk factors regularly after starting hormone therapy.

Doubts raised about cardiac risk

Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of Androgen Deprivation Therapy on Cardiovascular Disease and Diabetes. Journal of Clinical Oncology 2009;27:3452–58. PMID: 19506162.

Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular Mortality After Androgen Deprivation Therapy for Locally Advanced Prostate Cancer: RTOG 85-31. Journal of Clinical Oncology 2009;27:92–99. PMID: 19047297.

Kelly WK, Gomella LG. Androgen Deprivation Therapy and Competing Risks. Journal of the American Medical Association 2011;306:2382–83. PMID: 22147384.

Nguyen PL, Je Y, Schutz FA, et al. Association of Androgen Deprivation Therapy with Cardiovascular Death in Patients with Prostate Cancer: A Meta-Analysis of Randomized Trials. Journal of the American Medical Association 2011;306:2359–66. PMID: 22147380.

Roach M 3rd, Bae K, Speight J, et al. Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610. Journal of Clinical Oncology 2008;26:585–91. PMID: 18172188.

Combination hormone/radiation therapy

Hormone therapy is sometimes given in conjunction with external beam radiation to boost the effectiveness of treatment. Hormone therapy may also be used to shrink the size of large prostate glands (typically defined as those weighing more than 50 grams) before brachytherapy takes place, in order to enable proper placement of the radioactive seeds.

Combination hormone/radiation therapy is now a standard option for men with cancer that has extended beyond the prostate (stage T3 or T4) or whose cancer is considered high risk based on other clinical findings. The editor in chief of this publication strongly believes that combination hormone/radiation therapy is also preferable for intermediate-risk patients. (For a quick assessment of risk profiles, see Table 6.)

However, a study published in 2011 suggested that men with low-risk prostate cancer do not benefit from combination therapy. In that study, researchers from the Radiation Therapy Oncology Group (RTOG) — a national consortium of researchers funded by the National Cancer Institute — randomly assigned nearly 2,000 men with early, localized prostate cancer either to radiation alone or combined therapy (radiation plus four months of hormone therapy). At the 10-year mark, 62% of men assigned to combined therapy were still alive, compared with 57% assigned to radiation alone. Combination therapy decreased by half the chance that a man would die from prostate cancer. In the combination group, 4% of men died of prostate cancer during follow-up, compared with 8% of men who received only radiation.

Despite these favorable results, the role of hormone therapy in treating localized prostate cancer remains uncertain. Reanalysis of the data according to cancer risk subgroups showed that the greatest benefits were seen in men whose cancer was classified as intermediate risk. Men with low-risk disease did not benefit from combination therapy. (For results of this study and others that have looked at combination therapy, see Table 10.)

Table 10: Results of trials of combination hormone/radiation therapy

Study (recruitment years)

Participants

10-year overall survival

10-year prostate cancer mortality

Comments

European Organization for Research and Treatment of Cancer study (1987–1995)

415 men with high-risk prostate cancer

Radiation alone: 39%

Combination: 58%

Radiation alone: 30%

Combination: 10%

Hormone therapy continued for 3 years.

Scandinavian Prostate Cancer Group (1996–2002)

875 men with locally advanced prostate cancer (stage T3)

Radiation alone: 61%

Combination: 70%

Radiation alone: 24%

Combination: 12%

Tested 3 months of total androgen blockade followed by continuous flutamide treatment.

Trans-Tasman Radiation Oncology Group (1996–2000)

802 men with locally advanced prostate cancer (stages T2b to T4)

Radiation alone: 57%

Combination: 71%

Radiation alone: 22%

Combination: 11%

Benefits only seen with 6 months of hormone therapy; no benefit with 3 months of hormone therapy.

Radiation Therapy Oncology Group (1994–2001)

1979 men with localized prostate cancer (stages T1b, T1c, T2a, or T2b) and low, intermediate, or high risk of progression

Radiation alone: 57%

Combination: 62%

Radiation alone: 8%

Combination: 4%

Hormone therapy given for 4 months.

Benefit most pronounced in men with intermediate-risk prostate cancer.

No benefit to men with early-stage, low-risk cancer.

Sources: Bolla M, Van Tienhoven G, Warde P, et al. External Irradiation with or Without Long-term Androgen Suppression for Prostate Cancer with High Metastatic Risk: 10-year Results of an EORTC Randomised Study. Lancet Oncology 2010;11:1066–73. PMID: 20933466.

Denham JW, Steigler A, Lamb DS, et al. Short-term Neoadjuvant Androgen Deprivation and Radiotherapy for Locally Advanced Prostate Cancer: 10-year Data from the TROG 96.01 Randomised Trial. Lancet Oncology 2011;12:451–9. PMID: 21440505.

Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer. New England Journal of Medicine 2011;365:107–18. PMID: 21751904.

Widmark A, Klepp O, Solberg A, et al. Endocrine Treatment, With or Without Radiotherapy, in Locally Advanced Prostate Cancer (SPCG-7/SFUO-3): An Open Randomised Phase III Trial. Lancet 2009;373:301–8.

Caveats. One point to consider about combination therapy is that more advanced radiation techniques now enable doctors to safely deliver higher doses of radiation than were possible when many of these studies began. The RTOG study, for instance, started enrolling participants in 1994. The studies listed in Table 10 thus cannot determine whether combining androgen deprivation therapy with currently available higher-dose radiation provides any benefit above and beyond the radiation. In addition, some studies have tested three to four months of androgen deprivation therapy, while others have tested six months. So questions still remain about how valuable combination therapy is and whether adjusting treatment — such as providing a longer duration of hormone therapy in addition to radiation — may increase survival in men with localized prostate cancer.

Research now under way is testing hormone therapy combined with current radiotherapy methods, and may provide more answers. In the meantime, the editor in chief of this publication believes that for high-risk patients, hormone therapy should continue for at least two and possibly even three years. One observational study showed that an even longer duration of hormone therapy — lasting as long as five years — improved survival.

Side effects. Used on its own, hormone therapy often causes hot flashes, fatigue, and weight gain, and increases risk of cardiac problems. In addition, combined treatment is more likely than radiation alone to cause erectile dysfunction — and some research suggests that the problem may be less responsive to intervention to improve erectile function afterward.

The research is conflicting about whether any of these side effects persist in the long term. One 30-month study found that adjuvant hormone therapy worsened outcomes such as erectile dysfunction, urinary difficulties, and energy levels. However, another study that followed men for four years after combination therapy found that their long-term side effects did not differ significantly from those experienced by men who had undergone only radiation. And for the most part, both groups of men recovered erectile function and physical energy at about the same time. Until more is known, be aware that side effects do occur with combined therapy and it's important to discuss this issue with your doctor.

Research on combination therapy

Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer. New England Journal of Medicine 2011;365:107–18. PMID: 21751904.

Lawton CA, Winter K, Murray K, et al. Updated Results of the Phase III Radiation Therapy Oncology Group (RTOG) Trial 85-31 Evaluating the Potential Benefit of Androgen Suppression Following Standard Radiation Therapy for Unfavorable Prognosis Carcinoma of the Prostate. International Journal of Radiation Oncology, Biology and Physics 2001;49:937–46. PMID: 11240234.

Grant JD, Litwin MS, Kwan L, et al. Does Hormone Therapy Exacerbate the Adverse Effects of Radiotherapy in Men with Prostate Cancer? A Quality of Life Study. Journal of Urology 2011;185:1674–80. PMID: 21419449.

Chemotherapy

Over the past two years, chemotherapy options have increased for men with advanced cancer that is no longer responding to hormone therapy. (This situation is referred to as castrate-resistant prostate cancer.) In 2011, the FDA approved cabazitaxel (Jevtana) for metastatic castrate-resistant prostate cancer. This drug is also approved for use in Europe. (For more information about all the drugs available for advanced prostate cancer, see Table 11.) Several more chemotherapy compounds are well along in the drug development pipeline.

Cancer cells usually grow more rapidly than normal cells. Chemotherapy works against them by interfering with their growth and reproduction. Chemotherapy is therefore most effective for fast-growing malignancies that spread quickly. Although chemotherapy is often a standard treatment in other cancers, it is rarely used to treat early prostate cancer, which typically grows slowly for years. However, chemotherapy is routinely used for men with advanced cancer who no longer respond to other treatments.

Chemotherapy drugs for prostate cancer are given intravenously. They are usually taken in cycles, with each period of treatment followed by a rest period. This cycle can take place daily, weekly, or every three to four weeks, depending on the drug and your tolerance.

New drug. Cabazitaxel is the newest drug in the family of chemotherapy agents known as taxanes (a group that also includes docetaxel [Taxotere] and paclitaxel [Taxol]). Like these chemotherapy drugs, cabazitaxel inhibits cancer cell division and proliferation. The drug works in many men who have become resistant to these other drugs in the taxane family, and can extend survival.

Side effects. Because chemotherapy drugs are absorbed by tissues throughout the body, 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, chemotherapy 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. Both carboplatin and paclitaxel may cause myelosuppression, a reduction in the ability of the bone marrow to produce blood cells, causing anemia.

Table 11: Options for advanced prostate cancer

Drug name*

Common side effects

Comments

Standard chemotherapy (FDA-approved for prostate cancer)

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.

docetaxel
(Taxotere)

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

This anticancer drug may be used alone or in combination with other chemotherapeutic agents, such as estramustine and carboplatin. Docetaxel can extend survival.

Chemotherapy used "off label" (not specifically approved for prostate cancer, but often useful in alleviating 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.

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)

Although not specifically approved for the treatment of prostate cancer, paclitaxel can ease 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.

Other chemotherapy drugs

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.

mitoxantrone
(Novantrone)

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

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

Cancer vaccine

sipuleucel-T
(Provenge)

Fever, chills, fatigue, back pain, nausea, joint pain, headache

Extends survival in men who have exhausted other treatments. Expensive, so check insurance coverage ahead of time.

*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. Those that have not been approved by the FDA for the treatment of prostate cancer may not be covered by health insurance.

Drugs in development

A number of compounds are now in development. What follows is a brief look at the most promising.

Radium-223 chloride (Alpharadin) is designed to release a radioactive particle that targets prostate cancer metastases in bones. However, a phase III trial revealed that the compound also extended survival by about three months in men with advanced metastatic prostate cancer. Men taking placebo lived an average of 11 months after the study began, while men taking radium-223 chloride lived 14 months on average. Based on these results, the FDA granted fast-track review status to the drug in August 2011. FDA approval, if granted, might come as early as 2012.

Cabozantinib (an agent formerly known as XL-184) has also generated quite a bit of excitement among researchers, because it appears to do what no prostate cancer drug has done before — eradicate bone metastases in some men with advanced prostate cancer, at least temporarily. The agent, which can be taken orally (rather than intravenously like most chemotherapy), simultaneously targets at least two, and possibly more, chemicals that promote bone metastases. Researchers presented results from a phase II clinical trial at the American Society for Clinical Oncology annual meeting in June 2011. In a group of 108 men with bone metastases, the compound partially or completely eliminated bone metastases in 76% and stopped the metastases from growing in 21%. However, bone metastases became worse in 3% of men. The compound also reduced pain significantly. Among the men in the study who were taking narcotics to manage their cancer pain, 67% said they had less pain after taking this agent and 56% stopped taking narcotics or reduced the dose. Finally, the agent improved red blood cell counts in men with anemia. The agent remained effective for an average of 29 weeks. Keep in mind, however, that the research is still early. Many questions remain about who is most likely to benefit, what the dose should be, and how long effects will last.

MDV3100 is a potent anti-androgen that targets testosterone, the hormone that can fuel the growth and spread of prostate cancer. Whereas abiraterone inhibits the production of testosterone, MDV3100 blocks the ability of cancer cells to respond to this hormonal fuel. The compound is currently in phase III clinical trials. An interim analysis of one phase III study (the AFFIRM trial, which tested the agent in men who had previously had chemotherapy) found that MDV3100 extended average survival by nearly five months. The phase III PREVAIL study is currently enrolling participants who have not yet had chemotherapy.

TAK-700, like abiraterone, seeks to disrupt intracrine (within the cancer cell) production of testosterone. In a 12-week phase I/II trial involving 96 patients, TAK-700 reduced PSA levels by more than half in about 50% of participants. The agent is now in phase III clinical trials.

Vaccines and other types of immunotherapy

Unlike vaccines that prevent infections, cancer "vaccines" are designed to rev up the body's immune system in a way that helps fight advanced malignancies that no longer respond to other therapies. The first-ever FDA-approved cancer vaccine is for prostate cancer. The vaccine, sipuleucel-T (Provenge), is personally designed for each patient. Treatment involves removing white blood cells from the patient's blood and exposing them to an enzyme 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.

In the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial, a phase III study involving 512 men with advanced treatment-resistant cancer, sipuleucel-T prolonged survival by an average of four months (from an average of 22 months in the placebo group to 26 months in the vaccine group). At the three-year mark, 32% of men taking the vaccine were still alive, compared with 23% of those on placebo.

While sipuleucel-T may prolong survival, it's not entirely clear why patients are living longer. The drug doesn't induce a clinical response that doctors can measure — such as a drop in a man's PSA level, or the eradication of metastatic growths. It's also not clear how the drug affects the immune system. For these reasons, the drug is difficult for doctors to monitor.

Another thing to keep in mind is that this treatment is expensive — $93,000 for all three infusions. Although Medicare and some private insurers are covering the cost of this vaccine, it's wise to double-check before making a treatment decision.

Other vaccines are now in development. One of the most promising is PROSTVAC-VF, which works differently from sipuleucel-T. Instead of using a patient's cells, PROSTVAC-VF 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 reported in 2010, 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. 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.

Author: Harvard Health Publications
Date Last Reviewed: 2/1/2012
Date Last Modified: 9/23/2013
Copyright Harvard Health Publications