Denosumab is an FDA approved drug for treating bone metastases in men with prostate cancer. It works by acting as an inhibitor of RANK ligand (RANKL), a protein associated with progression of prostate cancer in bone. Studies show that men with metastatic prostate cancer who took Denosumab lived longer without skeletal-related events than men who take a placebo or other medicines for bone health.

Given the evidence for preventing skeletal-related events, some doctors  have theorized that Denosumab may also be able to prevent metastases in men whose cancer has not yet spread. A new study published in Lancet last month offers insight into this important question.

A multinational group of researchers recruited 1400 men from 30 countries with nonmetastatic castrate resistant prostate cancer (CRPC) to participate in a two year trial. The men were free of bone metastases at the start of the study but were all determined to be at high risk. The purpose of the trial, which was sponsored by the pharmaceutical company that manufactures and markets the product, was to determine if denosumab impacted the rate of bone metastasis as well as the overall survival rate of the participants.

At the start of the study, researchers randomly assigned the men to one of two groups. Every four weeks for two years, one group received injections of denosumab while the other group received a placebo. Periodic bone scans and skeletal surveys were used to measure bone metastases during the study.

At the end of the study, the researchers found that bone metastasis was significantly delayed in men who took denosumab compared to those who were given a placebo. The men who received the drug developed bone metastasis over four months later than their counterparts. The researchers also found, however, that while denosumab impacted bone metastasis, it did not impact survival rate in either group.

Although these results suggest denosumab may slightly delay metastases in some men with nonmetastatic prostate cancer, temporarily reducing the risk of skeletal-related events, the drug’s benefits may be outweighed by its costs.  The decision to prescribe this medicine will require careful consideration between the doctor and patient.

Denosumab is an expensive drug, costing nearly twice as much as traditional treatment for bone metastases.  It is also associated with risky side effects,  such as osteonecrosisof the jaw –bone death that causes pain, limited range of motion, and increased risk of severe arthritis —  and hypocalcemia— a calcium deficiency that damages bones and can be life-threatening if left untreated. With the possibility of only a slight delay in the development of metastases and no impact on survival rate, there is no clear cut recommendation that will be applicable to all patients.

Evidence to date does not support the use of denosumab as a preventive agent for bone metastases in men with prostate cancer. This trial, however, resulted in important knowledge about the role of RANKL inhibitors in bone metastases, and a better understanding of prostate cancer progression in general. Future research will build on this knowledge to clarify the role of denosumab as well as other bone modifying agents that affect bone health in prostate cancer patients.

More information on denosumab and the latest prostate cancer research can be found in the 2011 Annual Report on Prostate Diseases.

The SELECT trial was initiated after another study, known as the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Trial, found that men who took vitamin E experienced fewer prostate cancer diagnoses and fewer prostate cancer deaths than men who took a placebo. While these results were intriguing, because the ATBC study did not aim to study prostate cancer specifically, and included a limited sample of men, further research was needed.

The SELECT trial was designed to specifically examine the impact of vitamin E and another supplement, selenium, on prostate cancer risk. The study included 35,533 men ages 50 and older who did not have prostate cancer. Participants were randomly assigned to take daily pills that contained vitamin E, selenium, both, or neither. To determine the impact of supplements on cancer risk, the researchers planned to compare cancer rates among the four different groups over several years.

In 2008, after following the men for only five and a half years, the trial was stopped short. The study’s safety monitoring committee concluded that neither vitamin E nor selenium — alone or in combination — offered protection against prostate cancer. More importantly, however, they noted that the risk of developing prostate cancer in the vitamin E group was slightly higher than the risk in the other three groups. Though the difference in risk between the groups was not significant in a scientific sense, it was still threatening enough to stop the trial.

Now, seven years into follow-up, this worrisome trend persists. Only this time, the results are more definitive. A new data analysis published in the October issue the Journal of the American Medical Association reveals that the vitamin E group is the only group with a significantly higher rate of both aggressive and non-aggressive prostate cancer. Compared with the placebo group, men who took only vitamin E during the trial were 17% more likely to get prostate cancer over the seven-year period. The researchers were unable to offer an explanation of why taking the vitamin supplement increased cancer rates in these men.

Dr. Marc Garnick, an internationally renowned expert in medical oncology and urologic cancer, and editor in chief of the Annual Report on Prostate Diseases, offers readers some advice in light of these alarming results.

“We know that eating a healthy, balanced diet can help prevent prostate cancer. Based on the results of the SELECT trial, I strongly discourage my patients from taking supplemental vitamin E or selenium. In fact, I tell all my patients to throw away essentially every supplement they swear by; studies have generally not shown them to be helpful for disease prevention. Overall, if people eat a healthy diet, they really shouldn’t need supplements.”

The SELECT trial is the only large study thus far that has shown these results. More, longer-term research is needed to determine exactly why vitamin E might lead to greater prostate cancer risk. The trial’s scientists will offer blood and tissue samples from 3,500 men who participated in the trial to other scientists with an interest in further investigating the potential vitamin E and prostate cancer connection.

Read more about about prostate cancer and vitamin E on the Harvard Prostate Knowledge website.

Harvard’s Ann MacDonald, Editor of the Annual Report on Prostate Diseases, offers a summary of the issue along with expert advice for men on the Harvard Health Blog.

The federally funded study included nearly 370 moderately symptomatic men over age 45 from 11 North American hospitals. Over 72 weeks, the participants took a daily dose of either saw palmetto or a placebo. The standard dose of 320mg/day of saw palmetto was tripled over the course of the study. Despite this increase, at the end of the study period, saw palmetto did not relieve urinary tract symptoms any more than the placebo. These findings are consistent with findings from a one year trial in 2006 that also found no benefit of saw palmetto to patients with BPH symptoms.

A large majority of men have symptoms of an enlarged prostate at some point after age 50, which include frequent urination – including the need to visit the bathroom several times at night – difficulty urinating, and weak or intermittent urinary flow. While these symptoms are mild in some men, they are severe enough to interfere with quality of life in others. Medications to treat BPH are available but many can produce unpleasant side effects. Prior to this study, saw palmetto was thought to be a low-cost, safer alternative.

Study author and clinical professor of Medicine at Harvard Medical School, Michael Barry, MD, concludes “Saw palmetto extracts are commonly used by men with bothersome lower urinary tract symptoms, but our results indicate that the particular extract we tested was no better than a placebo at relieving those symptoms. It is possible that other formulations could be helpful, but a number of recent studies with negative results suggest it may be difficult to find a saw palmetto extract that is better than placebo.”

Health myths die hard. A recent article on healthy aging in the Washington Post suggested that taking vitamin E can help men prevent prostate and other cancers. That certainly isn’t what the evidence shows. In fact, a key clinical trial of vitamin E was stopped early because it showed that taking a vitamin E supplement failed to prevent prostate cancer and could—emphasis on could—promote prostate cancer.

Early cell culture and animal studies put a spotlight on vitamin E. Under controlled conditions, it was shown to slow prostate cancer growth. But as is so often the case in medical research, these results haven’t held up in humans.

Back in 1998, the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Trial raised hopes that taking vitamin E supplements could lower prostate cancer risk. (Alpha-tocopherol is the most active of the eight naturally occurring forms of vitamin E.) The trial found that men who took daily alpha-tocopherol supplements experienced 32% fewer prostate cancer diagnoses and 41% fewer prostate cancer deaths than men who took a placebo. While promising, these results weren’t considered conclusive. That’s because the ATBC trial wasn’t specifically designed to evaluate prostate cancer risk, and almost all of the participants were Caucasian smokers.

To clarify the ATBC results, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) was specifically designed to assess the effect of supplemental vitamin E on prostate cancer risk. As its name suggests, SELECT also looked at whether another antioxidant nutrient, selenium, affects cancer risk. All of the 35,533 participants were men aged 50 who did not have prostate cancer, and nearly one quarter were minorities. Participants were randomly assigned to take daily pills that contained alpha-tocopherol, selenium, both, or neither. The trial was initially planned to continue for 12 years, with five scheduled interim analyses.

At the second interim analysis in September 2008, the trial’s Data and Safety Monitoring Committee concluded that neither vitamin E nor selenium—alone or in combination—offered protection against prostate cancer. In fact, the monitoring committee noted that the rate of prostate cancer in the vitamin E group was slightly higher than the rates in the other three groups. The difference was not statistically significant, meaning it might have been due to chance, but the trend was worrisome. The committee decided to stop the trial early, and participants were told to stop taking their supplements in October 2008.

SELECT had some limitations. For example, the researchers did not test different doses or formulations of vitamin E.  But SELECT’s robust design and large number of participants make its results trustworthy.  The results are also likely to be widely applicable, due to the trial’s substantial proportion of non-white men and equal distribution of prostate cancer risk factors across all four study groups.

We know that eating a healthy, balanced diet can help prevent prostate cancer. Based on the results of the SELECT trial, I strongly discourage my patients from taking supplemental vitamin E or selenium. Though surprised, nearly all heed this advice and, in the process, many become more educated consumers of supplements and neutraceuticals.

Related content:
Cancer prevention trial (SELECT) comes to a halt

Video: Disappointing results for Vitamin E and selenium supplements

The study, published in the Journal for Health Care Quality, evaluated 400 randomly selected hospital Web sites. Researchers looked at the placement of information about robot-assisted surgery on the sites, claims about its risks and benefits, and the use of images or text provided by the robot’s manufacturer.

About two in five of the Web sites described the availability and mechanics of robotic surgery. Of these, 37% mentioned robot-assisted surgery on the home page and 66% cited information about the procedure within one click of the home page. Nearly three-quarters of the sites used industry-provided marketing materials or linked to the manufacturer’s Web site. When describing robotic surgery, nearly all of the hospital Web sites claimed clinical superiority to other surgical methods; one-third also reported improved cancer control. None of the sites noted any risks.

The number of patients undergoing robot-assisted surgery has grown 400% over the last four years. Advocates say that robotic procedures result in less pain, smaller incisions, and shorter hospital stays, but these claims are anecdotal. Currently, no long-term studies have been published that demonstrate any benefits.

Dr. Marty Makary, the study’s leader, questions how hospitals arrived at their claims about the robot’s benefits and voices concern about potential conflict-of-interest, given that robotic procedures typically cost more than traditional ones.

“The public regards a hospital’s official Web site as an authoritative source of medical information,” he said in a statement issued by Johns Hopkins. “Hospitals need to be more conscientious of their role as trusted medical advisers and ensure that information provided on their Web sites represents the best available evidence.”

Another study, presented at the American Urological Association’s annual meeting in May 2011, found that the number of prostatectomies performed between 2005 and 2008 increased by nearly 50%—even though the incidence of prostate cancer has declined. That dramatic change coincided with the introduction of robot-assisted procedures. In fact, robot-assisted surgery accounted for 15% of all prostatectomies in 2004, but more than 80% of them in 2008, implying that hospitals’ marketing efforts are working.

Sources: Jin LX, Ibrahim AM, Newman NA, et al. Robotic Surgery Claims on United States Hospital Websites. Journal for Healthcare Quality 2011. [E-publication.]

Lavery HJ, et al. Not a Zero-Sum Game: The Widespread Adoption of Robotics Has Increased Prostatectomy Utilization in the United States. American Urological Association 2011 Annual Meeting; abstract 76.

Published June 10, 2011.

Researchers followed 321 current smokers and 309 nonsmokers who had their prostate cancer treated with surgery between 1989 and 2005. Compared to nonsmokers, men who smoked were more likely to experience a rise in their prostate-specific antigen (PSA) level, a sign that cancer has returned; levels rose about 1% per pack-year smoked. (Smoking a pack of cigarettes every day for a year constitutes a pack-year; two packs a day for a year equals two pack-years.) Men who smoked 20 pack-years or more had the highest risk of recurrence. Also, recurrent cancers were larger and more aggressive in smokers than in nonsmokers.

“These data indicate that smoking history could provide valuable insight and should be included in risk-assessment models for prostate cancer,” said Dr. Joseph C. Presti, who presented the study’s findings.

Source: Ngo T, Lee J, Brooks J, et al. Smoking and Adverse Outcomes at Radical Prostatectomy. American Urological Association 2011 Annual Meeting; abstract 459.

Published June 10, 2011.

Last week I attended the Massachusetts Prostate Cancer Coalition’s 14^th annual symposium. I wasn’t exactly surprised that nearly every seat in the nutrition session was taken, given recent headlines that coffee may protect against prostate cancer development and that heart-healthy omega-3 fats might promote it. Perhaps everyone hoped to learn more about coffee and other “miracle” foods.

Nutritionist Sheila Wolfson

Boston-area nutritionist Sheila Wolfson focused on something more realistic but equally important—healthful eating once cancer has made its appearance. What she had to say about particular foods wasn’t exactly groundbreaking, but the way she linked diet to quality of life got the audience’s attention. Wolfson noted that men with prostate cancer (or anyone with cancer, for that matter) often feel that they have little control in their lives. But by choosing to eat healthfully, people with cancer can take control of their health, which can improve their attitude. By opting for more nutritious foods, people can create energy and vitality and enrich their quality of life.

Wolfson’s introduction made me think that she was about to rattle off a seemingly unending and overwhelming list of dietary changes that men with prostate cancer need to make without acknowledging how difficult this can be. Instead, she talked about what she ate growing up—lots of meat and few vegetables, mostly of the canned variety. She admitted that healthy eating doesn’t always come naturally and that people need to take small steps over time to be successful. Wolfson recommended three steps toward a more healthful diet:

• Eat more plant-based foods.
• Eat fewer foods from animals.
• Watch portion sizes and eat all foods in moderation.

A growing body of evidence shows that consuming high amounts of red meat and other food from animals, along with excess weight, raises the risk of certain diseases, including prostate cancer. That’s why Wolfson said people should fill two-thirds of their plates with plant-based foods such as vegetables, grains, fruits, legumes (beans), nuts, and seeds.

If you aren’t a vegetable fan, Wolfson offered another helpful tip: try one new vegetable or good-for-you food a week—and don’t give up if you don’t like it right away. “Kale might not be exciting to you the first time you try it, but keep working to make it palatable,” Wolfson said. “Try cooking it a different way, add it to soup, or find another recipe that you might like.”

When asked about dealing with a wheat allergy, Wolfson said that eating grains doesn’t necessarily mean having a slice of whole wheat bread. There are many non-wheat grains, including buckwheat, quinoa, barley, brown rice, corn meal, and rye. Because different grains contain different nutrients, one should strive to eat a variety of them. As for breakfast cereals, opt for whole-grain varieties with no more than 5 or 6 grams of sugar per serving. To sweeten cereal, add fresh fruit, such as blueberries.

Speaking of fruit, Wolfson said to choose fresh or frozen fruit, if possible, for higher nutritional value. Dried fruit is an option, but don’t overdo it because it’s generally high in sugar.

A healthy diet should also include legumes such as kidney beans, black beans, chickpeas and hummus, lentils, and natural peanut butter. Canned beans are easier to use than dried beans, but if you buy the canned variety, rinse the beans to remove excess salt, which can elevate blood pressure.

For many in the audience, the take-home message probably wasn’t new: it’s best to stick to a diet rich in plant-based foods. It isn’t as exciting a message as “coffee may protect against prostate cancer,” but it will probably have a bigger payoff in the long run.

Published may 25, 2011.

Through an Internet-based survey, 92 gay men from the United States and Canada answered questions relating to urinary, bowel, and hormone symptoms. Compared to their heterosexual counterparts, they reported worse physical and mental health functioning, poorer sexual and ejaculatory function, and a greater fear that their cancer would return.

“This is one of the early studies demonstrating that quality of life is more significantly impacted by prostate cancer in the gay population,” said Dr. Tomas Griebling, the AUA spokesman who moderated the press briefing.

Literature on this topic is limited; additional research may help determine why gay men experience the effects of prostate cancer treatment more acutely than straight men. Of note, these findings are considered preliminary because they have not yet been published in a peer-reviewed journal.

Posted May 25, 2011

Researchers at Henry Ford Hospital followed more than 3,300 patients between January 2005 and December 2009 and found that there were 368 complications in 326 of the patients. Most complications, such as intestinal obstruction, urinary tract infection, stomach pain, and internal bleeding, were considered minor and occurred within 30 days of the surgery. Of note, the study did not assess the procedure’s effects on urinary continence and erectile function, critical quality-of-life issues that patients need to consider prior to surgery. This is a major shortcoming of the study.

Older men with higher prostate-specific antigen (PSA) and Gleason scores, as well as those men with other medical problems, such as heart disease and gastroesophageal reflux disease, were more likely to suffer complications.

During RARP, a surgeon uses remote control to manipulate the robot’s arms, which are tipped with miniature tools, and remove the prostate through a tiny incision. The entire surgical team can view the operation using a 3-D monitoring system. Claimed benefits of RARP include less surgical trauma and shorter hospital stays (about one day in this study) and recovery times. But experts say that it can cost up to $2,000 more per patient compared with other surgical methods.

The researchers emphasized that surgical results depend on the experience of the surgeon controlling the robot, not the robot itself. In this study, the two lead surgeons had performed thousands of RARP procedures; less-experienced surgeons may have higher complication rates. The study did not compare RARP to other procedures, so whether it causes fewer complications than, say, an open prostatectomy or proves better at controlling cancer remains unclear.

Source: Argawal 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.

Published May 24, 2011