Population-wide prostate-specific antigen (PSA) screening for prostate cancer is not recommended in Australia, primarily because of the lack of large-scale randomised trial evidence of a beneficial effect on prostate cancer mortality and the known harms of overdiagnosis and unnecessary treatment that may ensue. In spite of this, PSA testing is common; the limited evidence available suggests that more than 50% of Australian men over the age of 50 years have had the test.1,2

In March 2009, the New England Journal of Medicine published the first articles from two large, randomised controlled trials to report on whether screening for PSA reduces the risk of death from prostate cancer.3,4 It was hoped that these long expected — albeit not final — reports from the European Randomized Study of Screening for Prostate Cancer and the prostate cancer component of the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (Box) would answer outstanding questions about the efficacy of prostate cancer screening.

In the European trial, 162 243 men aged 55–69 years were randomly allocated to receive an invitation to undergo PSA screening about once every 4 years or usual care. After a median of 9 years of follow-up, there were 71% more cases of prostate cancer and a 20% reduction in the risk of death from prostate cancer in those allocated to screening than in those receiving usual care (relative risk [RR], 0.80; 95% CI, 0.65–0.98), but no reduction in overall mortality (RR, 0.99; 95% CI, 0.97–1.02). In the US trial, 76 693 men aged 55–74 years were randomly allocated to receive an annual PSA test for 6 years and an annual digital rectal examination for 4 years, or usual care. After a minimum of 7 years of follow-up, there were 22% more cases of prostate cancer but no reduction in the risk of death from prostate cancer in those randomly allocated to screening compared with usual care (RR, 1.13; 95% CI, 0.75–1.70).

The trials have a number of notable differences, including length of follow-up, screening interval, PSA threshold for recommending biopsy, and proportion of the control group screened (Box). Although these differences prevent easy comparison of their results, it is important to note that the relative risks for prostate cancer mortality with screening do not differ significantly between the trials (χ12 = 2.19, P = 0.14), and that the 95% confidence interval about their summary relative risk, estimated using fixed-effects meta-analysis, includes unity (summary RR, 0.86; 95% CI, 0.71–1.03) (Box).

These trials have important limitations. First, their combined power is low, so that a moderate beneficial effect of screening cannot be established or excluded without longer follow-up or other trials. Moreover, in the US trial, although 85% of the screening arm had a PSA test, so too did 52% of the control arm. With only a 33% difference in screening between the groups, the power of the study to detect an effect of screening was substantially reduced. Screening in the control arm of the European trial was not reported.

Second, the trials are yet to report on other outcomes of PSA screening, including major treatment side effects, which are crucial to deciding whether large-scale screening is appropriate. The risk–benefit equation for PSA screening is complex. The major potential benefit is a reduction in risk of death from prostate cancer. The main risks are physical or psychological complications of screening and detection, overdiagnosis and concomitant treatment side effects, and unwarranted costs. Some elements of these risks were reported in the European trial. Overall, 16.2% of all PSA tests gave positive results and presumably led to biopsy, and 75.9% of these were found to be false-positives.4 The risk of undergoing radical prostatectomy in the screening group was nearly three times that in the control group (277 versus 100 per 10 000 men).5 To prevent one prostate cancer death, 1410 men needed to be screened, and 48 men needed to be treated.4 Although the number needed to screen compares favourably with that for breast6 and colorectal7 cancer, the issues around overdiagnosis are probably greater for prostate cancer. The cost-effectiveness of PSA screening is yet to be established. Even if it were shown to be favourable, the appropriate testing interval, target age range and PSA cut-off levels are not known. Hence, the persisting uncertainty about the effect of PSA testing on mortality is compounded by other outstanding questions.

What are the implications of the trial results for men and their doctors? The findings of these studies are finely balanced. Before they were reported, we had no valid randomised trial evidence; now we have evidence, but it is inconclusive and consistent with a modest but uncertain reduction in prostate cancer mortality at 10 years. Both trials can continue to inform us with longer-term follow-up and comprehensive assessment of all treatment outcomes.

What is the best advice that we can give now about PSA screening for prostate cancer?

Population-wide PSA screening should not be recommended. The findings from these two studies provide important evidence but are not adequate to allow a conclusion either for or against a benefit of screening. In addition, they reveal potentially high levels of overdiagnosis and its consequent costs and harm.

For individual men considering PSA screening, the potential risks and benefits should be carefully considered. Information from these trials and other studies, and data on the potential of treatments for localised prostate cancer to affect quality of life should be communicated, stating that uncertainty continues to cloud this issue. Clearly, men with a life expectancy of less than 10 years are particularly unlikely to benefit from screening, but those who wish to be tested after considering the evidence available should be given the test. Clinical practice includes treating patient concerns and worries, so that if a well informed man really wants to know whether he has prostate cancer, proceeding with PSA testing is a reasonable step. GPs play a crucial role in disclosing the uncertainties of PSA testing and in supporting men in their decision making.

Research assumes even greater importance when decision making is clouded by uncertainty. There is a clear need for more evidence on all effects of PSA testing. A greater understanding of decision making around PSA testing is also needed,8 as is better information to help men and their doctors address the issue.

Whether screening for prostate cancer lowers risk of death from prostate cancer remains uncertain. However, our uncertainty is increasingly based on evidence, which is far preferable to uncertainty based on ignorance.