What's risky about a PSA test?

You may wonder how getting a test for prostate cancer could have a downside. After all, there's little risk involved in the test itself — it requires simply drawing blood for evaluation in a lab. However, there are some potential dangers once the results are in. These include:

* Worry about false-positive results caused by elevated PSA levels from something other than prostate cancer.

* Invasive, stressful, expensive or time-consuming follow-up tests.

* False reassurance from a PSA test that doesn't reveal cancer (false-negative), leading to a missed diagnosis of aggressive prostate cancer that needs treatment.

* Stress or anxiety caused by knowing you have a slow-growing prostate cancer that doesn't need treatment.

* Deciding to have surgery, radiation or other treatments that cause side effects that are more harmful than untreated cancer.

What research is being done to validate and improve the PSA test?

The benefits of screening for prostate cancer are still being studied. The National Cancer Institute (NCI), a component of the National Institutes of Health, is currently conducting the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, or PLCO trial, to determine whether certain screening tests can help reduce the number of deaths from these cancers. The PSA test and DRE are being evaluated to determine whether yearly screening to detect prostate cancer will decrease a man’s chances of dying from this disease.

Initial results from the trial showed that annual PSA testing for 6 years and annual DRE testing for 4 years (performed in the same years as the first four PSA tests) did not reduce the number of deaths from prostate cancer through a median follow-up period of 11.5 years (range 7.2 to 14.8 years) (5). At 7 years of follow-up, a point in time when follow-up of the participants was essentially complete, 23 percent more cancers had been diagnosed in the screening group than in the control group. In the control group, men were randomly assigned to “usual care.”

These results suggest that many men were diagnosed with, and treated for, cancers that would not have been detected in their lifetime without screening and, as a consequence, were exposed to the potential harms of unnecessary treatments, such as surgery and radiation therapy. Nevertheless, it remains possible that a small benefit from the earlier detection of these “excess” cancers could emerge with longer follow-up. Follow-up of the PLCO participants will continue, therefore, until all participants have been followed for at least 13 years.

In contrast, initial results from another large randomized, controlled trial of prostate cancer screening, called the European Randomized Study of Screening for Prostate Cancer (ERSPC), found a 20 percent reduction in prostate cancer deaths associated with PSA testing every 4 years (6). At the time the results were reported, the participants had been followed for a median of 9 years. The average number of PSA tests per participant in ERSPC was 2.1. Most participating centers in this study used a lower PSA cutoff value as an indicator of abnormality than was used in the PLCO trial (3.0 ng/mL versus 4.0 ng/mL). As in the PLCO trial, many more cancers were diagnosed in the screening group than in the control group. The ERSPC researchers estimated that 1,410 men would have to be screened and 48 additional cancers would have to be detected to prevent one death from prostate cancer (6).

Scientists are also researching ways to improve the PSA test, hopefully to allow cancerous and benign conditions, as well as slow-growing cancers and fast-growing, potentially lethal cancers, to be distinguished from one another. Some of the methods being studied include the following:

* PSA velocity: PSA velocity is the change in PSA level over time. A sharp rise in the PSA level raises the suspicion of cancer and may indicate a fast-growing cancer. A 2006 study found that men who had a PSA velocity above 0.35 ng/mL per year had a higher relative risk of dying from prostate cancer than men who had a PSA velocity less than 0.35 ng/mL per year (7). More studies are needed to determine if a high PSA velocity more accurately detects prostate cancer early.

* PSA density: PSA density considers the relationship between the level of PSA and the size of the prostate. In other words, an elevated PSA level might not arouse suspicion if a man has a very enlarged prostate. The use of PSA density to interpret PSA results is controversial because cancer might be overlooked in a man with an enlarged prostate.

* Free versus attached PSA: PSA circulates in the blood in two forms: Free or attached to a protein molecule. The free PSA test is more often used for men who have higher PSA values. Free PSA may help tell what kind of prostate problem a man has. With benign prostate conditions (such as BPH), there is more free PSA, while cancer produces more of the attached form. If a man’s attached PSA level is high but his free PSA level is not, the presence of cancer is more likely. In this case, more testing, such as a prostate biopsy, may be done. Researchers are exploring additional ways of measuring PSA and comparing these measurements to determine whether cancer is present.

* Alteration of PSA cutoff level: Some researchers have suggested lowering the cutoff levels used to determine whether a PSA measurement is normal or elevated. For example, a number of studies have used cutoff levels of 2.5 or 3.0 ng/mL (rather than 4.0 ng/mL). In such studies, PSA measurements above 2.5 or 3.0 ng/mL are considered elevated. Researchers hope that using these lower cutoff levels will increase the chance of detecting prostate cancer; however, this method may also increase overdiagnosis and false-positive test results and lead to unnecessary medical procedures. (See ERSPC trial results above.)

What happens if my PSA level is high?

There are no hard and fast rules, and even the experts don't always agree on the best course of action. What happens next depends on whether or not you have any symptoms, your personal risk of prostate cancer, how high the PSA level is, and your age (the older you are, the higher your PSA level is likely to be whether or not you have prostate cancer).

As a rough guide, there are three main options after a PSA test:

* PSA not raised: Highly unlikely to have cancer. No further action.

* PSA slightly raised: Probably not cancer, but might need to repeat the test.

* PSA definitely raised: Probably need a biopsy to find out if you have prostate cancer.

What other methods are being studied to detect prostate cancer?

Researchers are investigating several other ways to detect prostate cancer that could be used alone or together with the PSA test and DRE. Some of these include the following:

* MicroRNA patterns: MicroRNAs are small, single-strand molecules of ribonucleic acid (RNA) that regulate important cellular functions. Researchers have found that the pattern of microRNAs in a cell can differ depending on the type of cell and between healthy cells and abnormal cells, such as cancer cells. Some research also suggests that the microRNA patterns in early-stage prostate cancer and late-stage prostate cancer may be different.

* Non-mutation gene alterations: The activity of a gene can be altered in ways that do not involve a change (mutation) to its DNA code. This can occur by modifying the gene’s DNA through a process known as methylation or by modifying the proteins that bind to the gene and help control how it is configured in the chromosome on which it is located. These types of gene alterations are called epigenetic alterations. Research has already shown that certain genes become hypermethylated and inactivated during the development and progression of prostate cancer. Scientists hope to identify DNA methylation changes and protein modifications that will be able to identify prostate cancer early and help predict tumor behavior.

* Gene fusions: Sometimes genes on different chromosomes can come together inappropriately and fuse to form hybrid genes. These hybrid genes have been found in several types of cancer, including prostate cancer, and may play a role in cancer development. The gene fusions found in prostate cancer involve members of the ETS family of oncogenes, which are genes that cause cancer when mutated or expressed at higher than normal levels. Researchers are investigating whether diagnostic or prognostic tests based on gene fusions can be developed.

* PCA3: PCA3, also known as DD3, is a prostate-specific RNA that is reported to be expressed at high levels in prostate tumor cells. It does not appear to contain the genetic code for a protein. A urine test for this RNA, to be used in addition to current prostate cancer screening tests, has the potential to be useful and is under study.

* Differential detection of metabolites: Molecules produced by the body’s metabolic processes, or metabolites, may be able to help distinguish between benign prostate tissue, localized prostate cancer, and metastatic prostate cancer. One such molecule, known as sarcosine, has been identified and may be associated with prostate cancer’s invasiveness and aggressiveness. Ongoing research is investigating whether a test based on sarcosine can be developed.

* Proteo-imaging: Proteo-imaging is the ability to localize and follow changes at the molecular level, through imaging, of the protein distributions in specific tissues. Being able to see different patterns of protein expression in healthy prostate tissue versus abnormal prostate tissue may help classify early prostate changes that may one day lead to cancer.

* Protein patterns in the blood: Researchers are also studying patterns of proteins in the blood to see if they can identify one or more unique patterns that indicate the presence of prostate cancer and allow more aggressive cancers to be distinguished from less aggressive ones.

Should I get a PSA test for prostate cancer?

A new study shows that screening for prostate cancer doesn’t necessarily save lives

Prostate cancer screening is about to get a whole lot cloudier.

Published this morning in the NEJM, the results of the study by the National Cancer Institute showed that, for men who were screened with both a PSA and digital rectal exam, there was no difference when compared to men who received “usual care.”

The results confirm the suspicions that many physicians already had, namely, that screening for prostate cancer does not appear to save lives.

As I have written countless times, there are many other diseases that can raise a PSA level. Combined with the fact that physicians have to act on elevated levels, this can lead to excessive prostate biopsies, as well as treating early cancers that end up not being the ultimate cause of death. All of these procedures expose the patient to a host of side effects, including bleeding and infection from the biopsy, and impotence and urinary incontinence from prostate cancer treatment.

The study was paired with the findings from a concurrent European study, which was not quite as negative. Nonetheless, the benefit of prostate cancer screening was minimal, with “7 fewer prostate cancer deaths for every 10,000 men screened and followed for nine years.”

Already, the USPSTF is shying away from endorsing prostate cancer screening by updating their guidelines last year, no longer recommending a PSA test for men older than 75.

So, what to do if you’re a patient? I think it’s more imperative than ever not to accept the dogma that “more screening is better medicine.” If anything, the decision of obtaining a PSA test needs to be thoroughly discussed with your doctor. Suddenly, the benefits of going down the path of screening doesn’t necessarily outweigh the risks.

Many may find that counterintuitive, and to be honest, it’s a hard truth to swallow. But these findings can help counter the pervading myth that obtaining every conceivable screening test is a sure way to improve health, when in actuality, it isn’t.