Commentary

PSA screening: Back to the future

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My urologic career began in the late 1980s, just before prostate-specific antigen (PSA) testing was introduced. Ever since, a busy prostate cancer practice has given me a frontline view of the benefits and possible harms of PSA screening.

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In the pre-PSA era, about half of men with newly diagnosed prostate cancer presented with incurable disease, either locally advanced or metastatic. The most common treatment was bilateral orchiectomy, which was the only safe form of androgen deprivation available.

Fast-forward a few years to the mid-1990s. Within 5 years after the introduction of PSA testing, the rate of incurable disease at diagnosis fell to just 5%, and treatment for localized disease skyrocketed, including radical prostatectomy, external beam radiation, and brachytherapy. As a result of earlier diagnosis and improved treatments, the death rate from prostate cancer in US men has fallen more than 30% since 1990.

The first-hand experience of seeing this massive stage migration to curable disease has forever convinced me that PSA screening is beneficial. Robust statistical models lend credence to this belief, with estimates that screening is responsible for 45% to 70% of this decline in mortality.1

Fast-forward again to 2012, when the US Preventive Services Task Force (USPSTF) published a strong recommendation against screening. The recommendation had so much force that as recently as 2014, only 11% of men at highest risk of prostate cancer in the Cleveland Clinic system were screened for it,2 mirroring national trends.

What happened? Colored by the experience in the era before PSA, when men presented frequently with painful metastatic disease and had an average life expectancy of 18 to 24 months, it was widely believed that all detected prostate cancer required treatment. What was not appreciated was that while PSA detects lots of prostate cancer, the most common reason for PSA levels to reach a range worrisome enough to trigger biopsy was actually benign prostatic hypertrophy.

The resulting increase in the number of biopsies resulted in the detection of a substantial number of low-grade cancers that were never destined to cause clinical harm but that got treated anyway, based on the fear that all cancers had metastatic potential. The USPSTF based its recommendation against screening on the harms caused by this overdetection and overtreatment of nonlethal disease, focusing on risks of biopsy such as sepsis, and on treatment-related adverse effects such as changes in urinary, bowel, and sexual function.

RANDOMIZED TRIALS SHOW A BENEFIT FROM SCREENING

As a result of this controversy, several large randomized trials designed to test whether PSA screening was beneficial were organized and begun in the 1990s, with one in the United States and another in Europe.3,4 Mature data from both trials have now established that there is indeed benefit to population-level screening.

The US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), was initially reported to show no difference in prostate cancer-specific mortality rates in those screened vs not screened, but because more than 90% of the men in the no-screening arm were screened anyway, that conclusion is erroneous.3

With 13-year follow-up and far less PSA contamination in the unscreened arm, the European Randomized Study of Screening for Prostate Cancer (ERSPC) in men ages 55 to 69 demonstrated a 27% reduction in the rate of death and a 35% reduction in the need for palliative treatments (androgen deprivation or radiation, or both) for metastatic disease in those screened vs not screened, clearly establishing substantial clinical benefit to PSA screening.4

A recent analysis of both trials that controlled for PSA drop-ins (comparing those actually screened with those actually not screened) concluded that the benefit of screening in terms of mortality reduction (estimated at about 30%) are equal in both trials.5 A large cohort study from Kaiser Permanente with 16-year follow-up has suggested that PSA screening has both a prostate cancer-specific benefit and an overall mortality benefit.6

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