Publication of apparently conflicting results from 2 large trials of prostate cancer screening has intensified the debate about prostate-specific antigen (PSA) testing and has led to a recommendation against screening from the US Preventive Services Task Force. This article reviews the trials and discusses the limitations of their empirical results in informing public health policy. In particular, the authors explain why harm-benefit trade-offs based on empirical results may not accurately reflect the trade-offs expected under long-term population screening. This information should be useful to clinicians in understanding the implications of these studies regarding the value of PSA screening.

Keywords

Prostate cancer

Mass screening

Clinical trials

Prostate-specific antigen

Simulation modeling

Public health policy

Key points

Introduction

The prostate screening odyssey has captivated researchers, policymakers, and clinicians since the late 1980s when the prostate-specific antigen (PSA) test was approved by the Food and Drug Administration for monitoring the progression of prostate cancer. The test was rapidly adopted for screening in the United States1 even as clinical trials to evaluate its efficacy in early detection were just beginning in the United States and Europe.

While the United States and European trials were ongoing, routine PSA screening became the standard of care in the United States, dramatically changing the profile of prostate cancer, and prompting concerns about overdetection and overtreatment of the disease. As rates of death from prostate cancer declined after the inception of screening, it became clear that policies for prostate cancer screening would have to carefully navigate the harm-benefit trade-offs of PSA testing. The results of the 2 large, randomized screening trials were eagerly awaited for what was hoped would be the final word regarding the lives saved and the price that would have to be paid for any screening benefit.

Five years after the publication of the primary trial results, there remains a vigorous debate about whether and how best to screen for prostate cancer. The randomized trial results were the basis for revised prostate screening recommendations from all of the major policy panels including the US Preventive Services Task Force (USPSTF),2 the American Cancer Society,3 and the American Urology Association.4 Whereas the USPSTF has recommended against PSA screening at all ages, the other panels have generally recommended shared decision making except for men with a limited life expectancy.

This article reexamines the trials and their findings in light of what needs to be known to develop policies for population screening. The authors first review the empiric results from the trials and ask what they inform us about (1) screening benefit, (2) screening harms, particularly overdiagnosis, and (3) the harm-benefit trade-offs of screening. Statistical and modeling analyses that go beyond the trial results are considered, and how these results may modify perceptions of the aforementioned outcomes is discussed. All screening outcomes depend on the screening strategy used, including the screening ages, intervals, and cutoffs for biopsy referral. Varying these parameters can dramatically alter the balance of harm and benefit; unfortunately, the 2 randomized trials are inherently limited in their ability to compare alternative screening strategies. The authors conclude that screening trials in general, and the Prostate, Lung, Colon, and Ovarian (PLCO) trial and European Randomized Study of Screening for Prostate Cancer (ERSPC) in particular, provide information that is critical for the development of screening policy, but cannot provide all the information needed for developing sound policies for population screening.

The large randomized prostate cancer screening trials

The 2 large screening trials, the United States–based PLCO cancer screening trial 5,6 and the ERSPC, 7,8 have been previously described in detail.

Several measures of screening benefit and harm are presented in the trial reports, and these are briefly reviewed here, as the manner by which harm and benefit are measured will significantly influence the perception of the value of screening. Several definitions are important in understanding screening outcomes. The relative screening benefit is expressed by the (prostate cancer) mortality rate ratio, which is the ratio of the risk of death from prostate cancer in the screened group relative to the control group over the follow-up period. The absolute screening benefit is expressed by the difference between the cumulative incidence of death from prostate cancer in the 2 groups, and may be thought of as an estimate of the lives saved by screening over the follow-up period. Both relative and absolute benefits are time-sensitive and generally increase with follow-up time. 9–11 Overdiagnosis is the detection by screening of cases that, in the absence of screening, would not have caused morbidity or mortality in the patient’s lifetime. Overdiagnosis may be expressed as an absolute number of overdiagnosed cases, as a fraction of the number screened, or as a fraction of screen-detected cases. Depending on how overdiagnosis is estimated, the results may also be highly time-sensitive. Finally, a measure of harm-benefit trade-off that has become fairly standard is the (additional) number needed to detect (NND) to prevent 1 death from prostate cancer, defined as the estimated overdiagnoses divided by the estimated lives saved by screening. The NND has been referred to as the additional number needed to treat to prevent 1 death from prostate cancer but this is not, strictly speaking, accurate, because not all newly diagnosed prostate cancers receive immediate treatment. The concept of the NND, a harm-benefit trade-off measure pertaining specifically to screening that carries the possibility of overdiagnosis, should be distinguished from the similarly named number needed to treat or NNT, which is a concept of benefit most commonly used in analysis of treatment trials.