What Is patientINFORM?

By Rebecca Viksnins Snowden

The debate over prostate cancer screening still rages on, despite the release of early results from 2 large randomized clinical trials investigating the issue in the New England Journal of Medicine today.

Since screening became fairly common in the early 1990s, the prostate cancer death rate has dropped. But the jury is out about whether that decline is the result of increased screening rates, improvements in treatment, or some combination of factors. To date, there have been no studies confirming that routine screening prevents deaths from prostate cancer.

The medical community had been eagerly anticipating results from these trials – one American, one European – which looked at whether prostate cancer screening, specifically testing with the prostate-specific antigen (PSA) blood test and digital rectal exam (DRE), saves lives. The trials had different designs and tested different populations. Neither found a large benefit from screening, although the final results will not be available for several years.

In fact, the studies may have raised more questions than they answer.

"For several years, many experts had anticipated these studies would show a small number of men will benefit from prostate screening, but a large number of men will be treated unnecessarily. And that's what these studies show," says Otis W. Brawley, MD, chief medical officer of the American Cancer Society. "However, the question is not as simple as: 'does prostate cancer screening work?' What we need to know is: what are benefits of prostate cancer screening and are they large enough to outweigh the harms associated with it? And despite the release of this early data, we still cannot say whether the benefits outweigh the risk."

In an accompanying editorial, Michael J. Barry, MD, says that the decision of whether to be screened should be based on ongoing conversations with your doctor – a recommendation that's in keeping with current American Cancer Society guidelines.

"These data show that what the American Cancer Society and other organizations have been recommending for many years still applies: that men at average risk should decide whether or not to be screened based on their own concerns and situation and after discussing the benefits and limitations of screening with their doctor," Brawley says.

A closer look at the studies

The first paper reports preliminary findings from the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, an ongoing project spearheaded by the National Cancer Institute. Researchers randomly assigned more than 76,600 men to two groups: the men either received "usual care" or had annual PSA tests for 6 years and digital rectal examinations every year for 4 years.

The researchers found little difference in prostate cancer death rates between the two groups at 7 years and again at 10 years of follow-up.

However, the study had some important limitations. Men in the control group weren't barred from getting screening tests, and many of them ended up getting screened anyway. In fact, by the sixth year of the trial, 52% of the men in the control group had had a PSA test and 46% had had a rectal exam. Further, because prostate cancer is slow-growing, an analysis of data that's only 7-10 years out may not give an accurate portrayal of the effectiveness of screening. Also, the authors used a PSA value of 4.0 ng per milliliter or more as their trigger for biopsy – a threshold that could miss some potentially lethal cancers. The authors also note that improvements in prostate cancer treatment over the years may have affected results.

In the European trial, known as the European Randomized Study of Screening for Prostate Cancer (ERSPC), researchers randomly assigned 182,000 men between the ages of 50 and 74 from 7 different countries to either a control group or a screening group, which required the men to have PSA screening on average every 4 years and a DRE twice over that period of time.

After a median follow-up of 9 years, the researchers found that screening reduced the rate of prostate cancer death by 20%. But, according to the authors, "1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer."

"When one considers all of the problems associated with treatment for prostate cancer -- urine incontinence, impotence, pain and bleeding among others -- that is a lot of men left with a lot of symptoms to save one life," says Len Lichtenfeld, MD, MACP, deputy chief medical officer of the American Cancer Society.

This study had several problems, too. For one, it wasn't a uniform study design. Many of countries used different study protocols, such as enrolling men of different age groups. Also, the researchers in most countries used a PSA cut-off value of 3 instead of 4, as in the American study. The result was that more European men were diagnosed with prostate cancer. The study also had some of the same issues that affected the PLCO study, namely that perhaps the researchers didn't track the patients long enough to accurately gauge the effectiveness of screening and that improvements in prostate cancer treatment over the years affected results.

However, in addition to collecting data on death rates, the European researchers are also evaluating the program's cost-effectiveness and the men's quality-of-life. That data is eagerly awaited.

Looking for a new test

Finding and treating prostate cancer early may seem like a no-brainer, but the issue is actually very complicated. Early prostate cancer is typically found using a PSA test and a DRE. There are limits to both methods, but the main issue is that even when these tests find a cancer, they can't tell how dangerous the cancer is. Some prostate cancers grow slowly and may never cause a man any problems, while others are more aggressive.

Because of a high PSA level, a man may end up being diagnosed and treated, even though his cancer may never have caused any symptoms. And his treatment, which may include surgery, radiation, or other treatments, can have serious effects on his quality-of-life.

"What this report tells us is that there may be some men who are diagnosed with prostate cancer and have the side effects of treatment, such as impotence and incontinence, with little chance of benefit," said John E. Niederhuber, MD, director of the NCI, of the PLCO study. "Clearly, we need a better way of detecting prostate cancer at its earliest stages and as importantly, a method of determining which tumors will progress."

Niederhuber was not directly involved in the research.

One promising – if preliminary – finding is that men whose urine contains a high concentration of a molecule called sarcosine appear to be more likely to have advanced prostate cancer, according to a recent study from University of Michigan researchers. The discovery could eventually lead to the development of a better tool for monitoring and treating prostate cancer.

The American Cancer Society is working to find a better test by funding prostate cancer research. As of February 20, 2008, the Society had 96 grants in effect totaling $54.2 million to support prostate cancer research. In 2008, the Society awarded 31 new prostate cancer research grants for $15.9 million.

Weighing benefits and risks

So, if you're a man in your 50s, should you being getting screened for prostate cancer?

The answer should come out of an ongoing discussion with your doctor. You should sit down together and weigh the benefits and risks.

"Our recommendation regarding prostate cancer screening is no different now than what the Society has been saying for years. Men need to talk with their health care professionals about the test," says Lichtenfeld.

If you're at a high risk for prostate cancer, you should start having that conversation as early as age 45. Men at high risk include African-American men and men who have a first-degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65). Men with several first-degree relatives diagnosed at an early age should begin the discussion at age 40.

For more information on this topic, see "Can Prostate Cancer Be Found Early?"

Reviewed by: Members of the ACS Medical Content Staff

"Screening and Prostate-Cancer Mortality in a Randomized European Study." Published online March 18, 2009 in the New England Journal of Medicine. First author: Fritz H. Schroeder, MD, Erasmus Medical Center, Netherlands.

"Screening for Prostate Cancer – The Controversy That Refuses to Die." Published online March 18, 2009 in the New England Journal of Medicine. Author: Michael J. Barry, MD, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.