PSA and Prostate Cancer: Between Guidelines and Practice

Paolo Spriano

December 09, 2022

The use of prostate-specific antigen (PSA) testing for prostate cancer screening remains the subject of scientific debate. Experts are unable to agree on how to balance the benefit of such testing regarding mortality rates with the potential harm caused by overdiagnosis.

The screening guidelines for prostate cancer are intrinsically challenging because of the naturally long, and often slow-growing, course of this disease. Screening performed too early or with a PSA threshold that is too low increases overdiagnosis, while screening too late or with a PSA range that is too high may not detect potentially treatable cases, which could end up being fatal. The risks and benefits of screening may also vary depending on age, race, and ethnicity.

Physicians must be made aware of the fact that, despite their best intentions, the guidelines may yield negative outcomes for patients with the disease. For example, following the 2012 US Preventive Services Task Force (USPSTF) recommendation statement against PSA-based screening for men of any age, there was a decrease in favorable pathology, an increase in unfavorable pathology, and negative outcomes post prostatectomy, particularly with respect to specific mortality.

Given that the route to a prostate cancer diagnosis often starts with the primary care provider choosing to conduct PSA-based screening, a question concerns whether recent and past evidence informs physicians on how to make the best decision for the patient.

Evidence-Based Findings

The evidence for PSA-based screening derives mainly from the (contested) results of two major randomized trials: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial, which after 13 years showed no reduction in mortality in the screening group, and the European Randomized Study of Screening for Prostate Cancer (ERSPC), which, for the same follow-up time, showed a significant relative reduction of prostate cancer mortality in comparison with the screening and the control group of 21% and 27%, respectively.

The 2012 USPSTF recommended against PSA-based screening of men in the general US population, regardless of age. This was because, although available data showed that screening saves lives, the number of lives saved was limited, and the proven harms of screening and treatment outweighed any potential benefits. In the years following the 2012 guidelines, this recommendation in the United States led to a reduction in PSA-based screening and, subsequently, a reduction in the number of people diagnosed with prostate cancer. A study conducted in nine referral centers for the management and treatment of prostate cancer in the United States documented that the proportion of low-grade Gleason score (GS) 3 + 3 cancers decreased significantly (30.2% to 17.1%), whereas high-grade GS 8 + cancers increased (8.4% to 13.5%). There was a 24% increase in absolute numbers of GS 8+ cancers. The task force subsequently reviewed its statement and promoted a decision-making process in which the decision is shared between the patient and the physician.

Scientific debate is focused on the critical interpretation of the results from the PLCO trial and on the high percentage of contamination of tests performed outside the study. It was clear that 44% of study participants had undergone PSA testing before randomization, and in the two arms of the trial, around 85% of participants had undergone PSA screening at least once. In a further review of the PLCO data that was published in The New England Journal of Medicine, this estimate was revised to 90%, which confirmed the limits and problems regarding the interpretability of the results of this trial.

The results from the ERSPC showed that one prostate cancer death could be averted per 781 men invited for screening, a better figure in comparison with that which led to the breast cancer screening recommendations: screening 10,000 women aged 50 to 59 years will result in eight (CI, 2 to 17) fewer breast cancer deaths. On the basis of evidence in favor of PSA-based screening for the prevention of prostate cancer deaths, this benefit is consistent with epidemiologic data, which, in the United States, showed a slight drop in specific mortality after PSA-based screening was introduced. Observational data showed that the advent of PSA-based screening also coincided with a smaller number of metastases, thus probably reducing morbidity and the costs associated with metastatic and locally advanced tumors.

Metastatic Cancer

Following the 2012 guidelines, various studies have shown a substantial reduction in the incidence of nonmetastatic prostate cancer that was associated with a reduction in PSA-based screening rates. However, since 2013, the reduction in the rate of nonmetastatic cases has been accompanied by a significant increase in the incidence of metastatic prostate cancer.

To determine whether the reduction in PSA-based screening rates in the 2005–2014 period was associated with a subsequent increase in the rate of metastatic prostate cancer, researchers conducted a cohort study of 4,678,412 men in 2005 and 5,371,701 men in 2019. All participants were patients in the US Veterans Health Administration (VHA). The study analyzed the change in PSA screening rates in 128 facilities and included the rates of prostate biopsy and the rates of nonmetastatic and metastatic prostate cancer cases occurring in the period 2005–2019. There was a 10% to 15% absolute decrease in PSA screening rates among veterans around the time of the introduction of the 2008 and 2012 USPSTF guidelines. Prostate biopsy rates and nonmetastatic prostate cancer incidence rates showed modest decreases that coincided with these changes in PSA screening and long-term nonscreening rates. The results suggested an association between lower facility-level PSA screening rates and higher metastatic prostate cancer incidence rates, which is consistent with findings from the ERSPC trial. That trial demonstrated a decrease in the incidence of metastatic prostate cancer in the PSA screening arm, compared with the usual-care arm.

Guidelines and Practice

In recent years, the process for expert review of guidelines has been diverted toward recommendations that account for individual risk for personalized PSA-based screening. The American Urological Association recommends PSA testing for men aged 55 to 69 years. For men aged 40 to 55 years, it recommends that decisions be individualized at an interval of ≥2 years. The American Cancer Society recommends screening from the age of 50 years for patients at medium risk and from around 40 years for Black American patients and those with a positive family history. It advises that PSA levels be used to determine the frequency of subsequent follow-ups. The National Comprehensive Cancer Network and the European Association of Urology recommend baseline PSA testing at age 40 years and that PSA levels be used to determine how often patients should be subsequently screened.

Today, there is a general feeling that the discussion of the benefit of screening has moved on somewhat. The current objective is to find a balance between the risks arising from overdiagnosis and the clear survival benefit achievable with PSA-based screening. From this point of view, the results emerging from the VHA study, in line with the ERSPC evidence, together inform physicians about making a joint decision on the potential benefits of PSA screening for men who wish to reduce their risk of metastatic prostate cancer.

This article was translated from Univadis Italy.

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