Tuesday, May 22, 2012

PSA Screening Benefits Few, Harms Many, Says Panel

A US government-sponsored panel of independent experts that reviews evidence and develops recommendations for preventive clinical services says the harms of PSA-based testing for prostate cancer outweigh the benefits. The recommendation has provoked a strong and angry response from many patient and medical groups.

In a report published early online before print in the 21 May of Annals of Internal Medicine, the US Preventive Services Task Force (USPSTF) writes of PSA-based screening for prostate cancer: "[it] may benefit a small number of men but will result in harm to many others".

The USPSTF is a group of primary care physicians and epidemiologists that is appointed and funded by the US Department of Health and Human Services' Agency for Healthcare Research and Quality (AHRQ). Its recommendations are important because they influence how health policy is shaped and what insurers do. For instance, it is empowered by the Affordable Care Act to decide which screenings Americans receive.

This recommendation is the task force's "final word" on PSA-based testing. It follows a period of public comment after its last published recommendation in 2008, when at the time it concluded there was no evidence to support PSA testing for men over 75.

The task force says it has since then reviewed the evidence published since 2008 and concluded that the harms of PSA-based testing outweigh the benefits, regardless of age. The task force does not take costs into account when developing recommendations: it just weighs health benefits against harms.

The task force posted a draft of this final recommendation for public comment in October 2011. At the time it gave PSA-based screening a "D" grade, which means doctors should not offer the test to their patients because there are more harms than benefits.

Many who commented at the time suggested the "D" be changed to a "C" which says doctors could offer the test to patients who ask for it. But the panel has not changed its draft recommendation, and has stuck to the "D" grade.

According to its Annals of Internal Medicine report, the task force considered two major trials that assessed the life-saving benefits of PSA-based testing in asymptomatic men.

The first trial took place in the US. It did not show that PSA-screening reduce deaths to prostate cancer. The second trial took place in seven European countries and found PSA screening reduced deaths by one death per 1,000 men screened in a subgroup aged 5 to 69 years, mostly in two countries. The other five countries did not find a statistically significant reduction deaths.

The task force reports there is strong evidence that PSA-based screening can be harmful.

Just under 90% of men whose prostate cancer is detected via PSA undergo early treatment, either with surgery, radiation, or androgen deprivation therapy, they write. They say the evidence shows up to 5 out of every 1,000 men die within 1 month of surgery, and between 10 and 70 that survive have to live the rest of their lives with urinary incontinence, erectile and bowel dysfunction.

Monday, May 21, 2012

Statins may slow prostate growth

Statins drugs prescribed to treat high cholesterol may also work to slow prostate growth in men who have elevated PSA levels, according to an analysis led by researchers at Duke University Medical Center.

The finding, presented at the annual meeting of the American Urological Association, provides additional insight into the effects of cholesterol-lowing drugs such as statins on the prostate. Previous studies at Duke and elsewhere had found a link between statins and lower levels of PSA, a protein produced by the prostate that is often elevated by cancer or by non-lethal prostatic diseases.

In the current finding, prostatic growth rate diminished among men with elevated PSA levels who took statins, although that effect was relatively small and tapered off after about two years.

"Given that prostate enlargement is an important health problem in the United States and elsewhere, and will be a larger problem as the population ages, it's important to understand and treat its causes," said Roberto Muller, M.D., a urology fellow at Duke and lead author of the study.

Enlarged prostate, most commonly diagnosed as benign prostate hyperplasia, causes urinary problems that can escalate to bladder and kidney damage. Up to 90 percent of men over the age of 70 have some symptoms associated with enlarged prostate, according to the National Institutes of Health.

Muller and colleagues used data gathered for an unrelated, large trial originally testing whether a drug called dutasteride could help reduce the risk of prostate cancer. To test their hypothesis that statins may be associated with slower prostate growth, the researchers culled the data of more than 6,000 men, including 1,032 who also took statins.

Men on statins tended to be older than non-users, and thus were expected to have greater prostate sizes. But prostate sizes were actually similar between statin users and non-users at the start of the study. That finding provided the first suggestion that statins might affect prostate growth.

When changes in prostate growth were compared two years after the start of the trial, men in the study who took a statin drug had less prostate growth, regardless of whether they had been randomly assigned to take dutasteride or a dummy pill. Prostate growth was an average 5 percent less in men who took both a statin and dutasteride pill compared to men who took only dutasteride. For those taking a statin and a dummy pill, prostate growth was 3.9 percent less than for men taking only the placebo.

Those reductions, however, did not persist after two years.

"We don't yet understand the mechanisms that might be causing this," Muller said. "Some have suggested that statins may have anti-inflammatory properties, and inflammation has been linked to prostate growth, but this needs further study."

Muller said the findings in the current research also suggest that lifestyle choices such diet and exercise may not only affect cholesterol, but also prostate health.

"Prostate enlargement was once considered an inexorable consequence of aging and genetics, but there is growing awareness that prostate growth can be influenced by modifiable risk factors," Muller said. "In this context, the role of blood cholesterol levels and cholesterol-lowering drugs such as statins warrants further study."

Vitamin D + TB Vaccine: Allies in Fight Against Bladder Cancer?

The tuberculosis vaccine is often used as a treatment for bladder cancer, and adding vitamin D might improve the vaccine’s effectiveness, according to new research from the University of Rochester Medical Center presented today at the American Urological Association annual meeting.

Yi-Fen Lee, Ph.D., associate professor of Urology at URMC, has conducted a pre-clinical study in a mouse model showing that a combination of vitamin D therapy and the Bacillus Calmette-Guerin (BCG) vaccine greatly improves bladder cancer survival. The next phase, an early clinical trial in patients, will begin soon as part of a collaborative research project between the URMC’sJames P. Wilmot Cancer Center and the Roswell Park Cancer Institute in Buffalo.

The connection between vitamin D and tuberculosis was established long ago, when ancient societies sent people with TB into the sunlight for therapy. Increasing vitamin D levels is known to wake up cells and trigger an immune response whenever infection or inflammation is present.

Also well established is the use of the TB vaccine to treat several forms of bladder cancer. The vaccine works by pushing the body’s immune system to fight the cancer cells. However, approximately 30 to 40 percent of people with bladder cancer who receive the vaccine do not respond to it.

Lee is investigating whether a lack of vitamin D in these patients might explain the poor response.

Prior studies have shown that BCG, the modified bacteria that causes TB, turns on a toll-like receptor signal that makes more vitamin D receptors and induces a key enzyme that converts to the most potent, bioactive form of vitamin D, or 1,25-hydroxylvitamin D3. So Lee thought it was likely that boosting the levels of vitamin D in the body would activate this process, enhancing the vaccine.

The mouse study involved four arms: a control group, a group that received vitamin D treatment alone, a group that received BCG treatment alone, and a fourth group that received the combination of vitamin D and the BCG vaccine. The latter (combination therapy) group was the only group in which 100 percent survived bladder cancer, Lee said.

“Vitamin D appears to be critical to the success of BCG immunotherapy,” Lee said, although she does not advise taking high doses of vitamin D unless under medical supervision. “Just as importantly, though, we have shown the migration and signaling involved in establishing vitamin D as a biomarker that can be easily measured.”

Monday, May 7, 2012

Oral Vitamin D Supplements Fight Prostate Cancer

Higher oral doses of plain vitamin D raised levels of calcitriol in prostate tissue. Higher prostate levels of calcitriol, a hormone made from vitamin D, corresponded with lower levels of the proliferation marker Ki67 and increased levels of cancer growth-inhibitory microRNAs in prostate cancer cells.

The results not only point to the mechanisms by which vitamin D affects the rate of prostate cancer growth, but also indicate that vitamin D may slow the growth of prostate cancer cells — a key finding given that the role of vitamin D in prostate cancer has been “controversial, with some suggesting that higher levels of vitamin D should be avoided,” said Reinhold Vieth, Ph.D., professor at the University of Toronto in Toronto, Ontario, Canada.

“This study shows calcitriol makes the foot come off the gas pedal of cancer growth. We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign,” said Vieth. “We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer.”

Vieth and colleagues previously reported that in men who were being monitored regularly for prostate cancer, higher vitamin D levels slowed the rate of rise in prostate-specific antigen levels. They randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in doses of 400, 10,000 or 40,000 IU for three to eight weeks before surgery. Researchers found that calcitriol levels in the prostate increased progressively with each daily dose of vitamin D, with 40,000 IU showing the highest levels. These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth, as well as higher levels of specific growth-inhibitory microRNAs.

Vieth stressed that he and his colleagues do not advocate vitamin D supplementation in doses higher than 4,000 IU daily. Patients were assigned to the 40,000 IU daily dose because of the short presurgical time frame available for study, not as a regular regimen.

“Plain vitamin D provides the raw material to permit the body to take care of its own needs,” he said. “We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes.”

The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a “high” dose of plain vitamin D.