Prostate cancer screening: Why the controversy?

PLCO and ERSPC comparison

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2 large studies, no clear conclusions

In 2009, early results from two major studies regarding prostate cancer screening were released in the New England Journal of Medicine. In these studies, a total of more than 250,000 men were randomized to screening and followed for prostate cancer death.

These studies have formed the basis for most prostate cancer screening recommendations, yet they are commonly misunderstood. To better assess the implications of these studies, it's important to review study design, strengths and weaknesses in order to place them in context within the larger debate on prostate cancer screening.

PLCO

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, a study based in the United States, randomized 76,693 men ages 55 to 74 to either annual screening with PSA and digital rectal examination or usual care.

In this study, approximately 17 percent more cancers were detected in the screening arm than in the control arm, but there was no difference in cancer-specific death.

Although technically randomized, a criticism of the study is that it doesn't appear to have been particularly well controlled:

• Nearly two-thirds of men randomized in the study underwent PSA screening prior to entry into the study, a factor that undoubtedly eliminated high-risk cancers before the study even began. This limitation has led many to suggest that the trial was destined to fail from the start.
• Only 85 percent of men in the screening group were compliant with screening, while 52 percent of men randomized to the control arm underwent screening as a part of usual care.
• Only 31 percent of men with an abnormal digital rectal examination and a PSA of more than 4 ng/mL underwent prostate biopsy.

These data call into question the reliability of the study's findings — the screening and control groups essentially blended together, reducing the study's ability to detect a difference between the two groups.

ERSPC

The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial was a randomized screening study based in Europe. In this study:

• 182,000 men were randomized to be either controls (no screening) or receive screening with digital rectal exam and PSA every four years
• 39 percent more cancers were detected in men in the screening group than the control group
• There was a 20 to 31 percent reduction in prostate cancer death in the screening arm compared with the control arm

ERSPC suffers from fewer of the limitations of PLCO. Specifically, very few men were screened prior to entry into the study and contamination of the control group was significantly lower at 15 percent. Compliance with biopsy recommendation was also much higher at 85 percent.

ERSPC has been criticized for lack of informed consent in many of the countries, however, and many more screened men opted for active surveillance in ERSPC than in PLCO (18 percent vs. 11 percent).

Finally, although there was a significant benefit to screening, nearly 1,400 men needed to be screened and 48 men treated to save one life after eight years. It should be noted, though, that with longer follow-up and further prostate cancer-related deaths, the number of men needed to be screened and treated to prevent one death will very likely decrease.

Practical considerations

While ERSPC and PLCO both had similar endpoints and objectives, the manner in which the studies were performed and their interpretation were widely divergent. Nonetheless, there are important, complementary data that emerged from both trials:

• First, prostate cancer investigators now have a much better understanding of PSA dynamics on a population scale. This knowledge includes the complicated issues surrounding contamination and the difficulties in performing large studies where researchers are trying to obtain something as simple as a serum PSA.
• Also, both studies have demonstrated that men with a very low PSA (0-1.0 ng/mL) are at low risk of developing a clinically significant prostate cancer within the next several years.

The diversity of methodology and data from these trials allows for significant flexibility in their interpretation, which makes it difficult to use them to substantiate across-the-board recommendations. Rather, the decision of whether to screen or not screen — using PSA testing or other means or both — is a decision best made between physicians and their individual patients.

"In making this decision, both physicians and their patients should be informed of the benefits and risks of screening or not screening. Other clinical factors, such as age, comorbidities, 10-year life expectancy and patient preferences, should also be taken into account. By being fully informed, patients and physicians are better armed to combat prostate cancer," says Erik P. Castle, M.D., a urologic surgeon at Mayo Clinic in Arizona.

References

Andriole GL, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine. 2009;360:1310.

Andriole GL, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: Mortality results after 13 years of follow-up. Journal of the National Cancer Institute. 2012;104:125.

Schroder FH, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine. 2009;360:1320.