The Case Against PSA-based Screening

Screening with prostate specific antigen (PSA) blood testing is used by more than 60% of men over age 50. Despite this, controversy swirls around its use for this purpose, stemming from disagreements on whether and by how much it truly benefits men with regard to prostate cancer, and because of the major consequences, both physically and economically, of diagnostic work-ups and treatment for those who are screened. Two huge randomized trials were conducted with the hope that their results would resolve the issue one way or the other, but their recent publication has done little to quell the concerns and opinions of those on either side. We present pro and con articles to outline key issues on each side of this debate.

Although it is clear that PSA testing is very effective in finding prostate cancers, it is less clear that it reduces deaths from this disease, the true measure by which we should judge a screening test. In fact, the results of two milestone studies on this topic, one from the United States(1) and one from Europe(2) together provide no evidence for the routine screening of adult men by serum prostate specific antigen (PSA) testing on an annual basis.

The Prostate, Lung, Colon and Ovary (PLCO) trial enrolled nearly 77,000 men, ages 55-74, from 10 centers across the United States; annual PSA screening to a total of 6 screens and annual digital rectal examinations were offered to the screened group, usual care to the controls (1). The results of screening were reported to the participants and their physicians, who decided on subsequent management. Many were placed on regular PSA surveillance, though by 4 years over 80% of those with positive tests had achieved resolution (biopsy, or PSA falling to lower levels) (3).

The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men from Belgium, Finland, Italy, the Netherlands, Spain, Sweden, and Switzerland (2). In all countries, men ages 55-69 were included, in one men age 50-54 were also included, and in four countries men up to age 74. Two PSA screens at 4-year intervals were offered except in Sweden, where the interval was two-yearly. Immediate biopsy of those with an abnormal PSA was encouraged; treatment was given according to community standards.

In both trials, there was no reduction in deaths from prostate cancer in the first 7 years after randomization in the screened group compared to the control group (1, 2). In PLCO, at ten years, with 67% of the enrolled followed, there were 92 deaths from prostate cancer in the screened group compared to 82 in the control (a non-significant difference). No data beyond 10 years were reported for PLCO. In ERSPC, at 10 years, less than a third of those randomized had been followed. However, in total at 14 years there were 261 deaths from prostate cancer in the screened group compared to 363 in the control, a nonsignificant 15% reduction in deaths; for men age 55-69 the reduction was 20%, which was just significant.

The PLCO trial was conducted against a background of persistent, long-term advocacy of PSA screening * (4, 5). Forty-five percent of those randomized had had at least one PSA test in the 3 years preceding randomization, and in the control group overall an estimated 52% had a PSA test. Nevertheless, PSA screening was substantially higher in the screened group throughout than in the control. In ERSPC, the extent of PSA screening in the control group was 30% in the Netherlands, data are not available for other countries (6). Lower PSA cut-off levels were applied in ERSPC, which led to higher detection rates of prostate cancer and substantially more over-diagnosis than in PLCO. An estimated 66% of screen-detected prostate cancers in the Netherlands were over-diagnosed, that is, in the absence of PSA screen detection, they would never have presented clinically in that person’s lifetime (7).

Even the reduction in prostate cancer deaths was achieved as a result of great effort, since 1,410 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 (2).

Furthermore, treatment differences between the arms in ERSPC, which did not occur in PLCO, could explain the reduction in deaths. It is relevant that the wide application of improvements in prostate cancer treatment is probably largely responsible for declining prostate cancer mortality rates in most countries (8). Reductions in prostate cancer mortality have been greater in the USA than any other country. This probably explains why prostate cancer mortality was lower in the control group of PLCO than in the screened group of ERSPC.

It is clear that PSA screening, if aggressively applied, results in a massive burden of unnecessary treatment and complications for patients, with minimal if any reduction in prostate cancer mortality. There is good evidence from PLCO that if a man has a PSA level below 4 ng/ml and a negative digital rectal examination, the probability of prostate cancer in the next 5 years is very low (3). Currently therefore, in North America, there is no justification for PSA screening to be intensified, indeed, fewer tests and more caution over management of detected prostate cancers is highly desirable (4).

REFERENCES

1. Andriole GL, Grubb RL, Buys SS, Chia D, Church TR, Fouad MN, Gelmann EP, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, Crawford ED, O’Brien B, Clapp JD, Rathmell JM, Riley TL, Hayes RB, Kramer BS, Izmirlian G, Miller AB, Pinsky PF, Prorok PC, Gohagan JK, Berg CD for the PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. New Engl J Med 360:1310-19, 2009
2. Schröder FH, Hugosson J, Roobol MJ, Tammela TLJ, Ciatto S, Nelen V, Kwiatkowski M, Lujan M, Lilja H, Zappa M, Denis LJ, Recker F, Berenguer A, Määttänen L, Bangma CH, Aus G, Villers A, Rebillard X, van der Kwast T, Blijenberg BG, Moss SM, de Koning HJ, Auvinen A, for the ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. New Engl J Med 360:1320-28, 2009
3. Grubb RL, Pinsky PF, Greenlee RT et al. for the PLCO Project Team. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int102:1524–30, 2008
4. American Urological Association (AUA). Prostate-specific antigen (PSA) best practice policy. Oncology (Williston Park) 14(2):267-72, 277-8, 280 passim, 2009
5. American Cancer Society, Cancer Screening Guidelines 2008. Accessed Jan. 5, 2009 at: http://www.cancer.org/docroot/ped/content/ped_2_3x_acs_cancer_detection_guidelines_36.asp
6. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R, Feuer E, de Koning H. Lead Time and Overdiagnosis in Prostate-Specific Antigen Screening: Importance of Methods and Context. J Natl Cancer Inst 101:374-383, 2009
7. Etzioni R, Feuer E. Studies of prostate cancer mortality: caution advised. Lancet Oncol 9:407-9, 2008
8. Klotz L. Active surveillance for favorable-risk prostate cancer: who, how and why? Nature Clinical Practice Oncology 4:692-698, 2007