Perspective on Prostate Cancer Screening
Year: 2018
Type: article
Abstract: Undoubtedly, no biomarker has had more profound impact on our approach to cancer detection, staging, and monitoring after treatment than the prostate-specific antigen (PSA)7 test. PSA is a serine protease produced by the prostate epithelium, secreted into seminal fluid, and measurable in peripheral blood by immunoassay laboratory techniques detecting both free unbound forms and that bound to the protease inhibitor α1-antichymotrypsin. The introduction of the PSA test as a diagnostic means to monitor and detect prostate cancer during the 1980s was based on discoveries in the laboratories of Kuriyama, Wang, and Papsidero, together with observations in clinical cohorts never exposed to screening by Stamey, Catalona, and others, noting that men with prostate cancer (or benign prostatic hyperplasia) had higher PSA concentrations compared with healthy controls (1). The PSA test was far more sensitive than assays of prostatic acid phosphatase and digital rectal examination. These findings set off a rapid widespread introduction of the PSA test in clinical practice, mainly in the US, which contributed to a dramatic surge in prostate cancer incidence in the US during the late 1980s through the mid-1990s. There is clear evidence from large population-based randomized trials—the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Göteborg randomized screening trial—that early detection (and concomitant management) by PSA screening reduces a man's risk of dying from prostate cancer. Indeed, extensive use of PSA testing has importantly contributed to a 40% to 50% decline in prostate cancer mortality in the US between 1993 and 2015. However, the widespread use of PSA testing of asymptomatic men, combined with liberal criteria to perform a prostate biopsy, has led to important harms associated with the overdiagnosis of tumors that would never have caused symptoms or harm during a man's lifetime, as well as consequential risk of unnecessary treatment. Because the prostate gland is anatomically located near nerves controlling erection, the urinary bladder, and rectum, curative treatment with surgery or radiation may severely impair normal functioning, including impotence, urinary leakage, and bowel dysfunction, which may dramatically reduce quality of life. For these reasons, health policy decision-makers and guideline groups worldwide have long held a restrictive attitude to organized population-based PSA screening and have issued recommendations against this practice. To date, population-based screening programs for prostate cancer are in place only in Lithuania and Kazakhstan. In 2012, the United States Preventive Services Task Force (USPSTF) sought to put an end to indiscriminate use of PSA testing in the US, concluding that “there is moderate certainty that the benefits of PSA-based screening for prostate cancer do not outweigh the harms.” The guideline group assigned a “grade D” to the service, thus recommending against PSA screening for men of all ages. This guideline, followed by most primary care physicians in the US, has importantly influenced contemporary PSA testing practices leading to a noticeable decrease in PSA testing rates, prostate biopsies, and management (2). Although it may not have been the intended consequence, the age-adjusted prostate cancer incidence rates in the US are now back at square one, and remarkably comparable with the pre-PSA-era levels in the 1980s. The 2012 USPSTF evidence review has been heavily criticized by many and contains multiple errors of facts, statistics, and interpretation, for example, drawing conclusions based on incomplete data from the ERSPC trial, pooling data from incompatible trials, overestimating the risks of radical prostatectomy, and including overall mortality as an end point when its power is much lower than cancer-specific mortality (3). In 2017, the USPSTF reviewed and reconsidered the published evidence (with a final recommendation published in 2018) (4). This time, the task force solicited input from subject-matter experts in urology, a step that was missed in 2012. The USPSTF also considered the clear evidence from longer-term follow-up from the ERSPC trial (13 years) showing that PSA screening contributes to significant risk reductions of both metastatic disease and prostate cancer-specific mortality. There was also longer follow-up from a randomized trial comparing surgery vs observation for early-stage prostate cancer (the PIVOT trial) and documented evidence of increased utilization of active surveillance for low-risk prostate cancer, a strategy to carefully monitor the cancer and delay curative treatment in the absence of signs of progression, thereby alleviating some of the adverse effects of active treatment. The panel also reviewed the evidence for risk-stratified approaches to screen men with higher than average risk (e.g., African-American men and those with family history) and acknowledged modeling studies in estimating the risk of overdiagnosis. Thus, access to more evidence on the benefits of screening tipped the scale in 2017, leading the USPSTF to conclude with “moderate certainty that the net benefit of PSA-based screening for prostate cancer in men aged 55–69 years [the core age-group of the ERSPC trial] is small for some men”—and, therefore, upgrade their recommendation on PSA screening to a “grade C”—recommending that physicians and men of this age engage in shared decision-making when discussing the pros and cons of PSA screening, as men's preferences for benefits and harms may vary. This stance now puts the USPSTF recommendation in line with mainstream academic thought and that of many other guideline groups, including the American Urological Association. Although the updated 2017 USPSTF recommendation for men ages 55 to 69 years is a major sea change, in our view, this recommendation is still limited by relying predominantly on randomized trial data and by ignoring studies that address the question not so much as to whether PSA testing does more harm than good, but the question of how to shift the balance between harms and benefits. The USPSTF still disregards a large body of evidence from large-scale, well-conducted prospective cohort and case–control studies with >2-fold longer follow-up than the ERSPC trial and performed in areas where rates of PSA testing were low, such as the Preventive Project in Malmö, Sweden, demonstrating the value of a midlife baseline PSA as a strong risk predictor decades ahead of the subsequent documented evidence of distant metastasis or death from prostate cancer. We have previously shown that the net benefit of PSA screening is an average of 2 extreme PSA subgroups, with the benefits of regular screening being high among the group of men with a PSA level ≥2 ng/mL at age 60 years, whereas continuing to screen men with PSA level <1 ng/mL at age 60 years is associated with a substantial risk of overdiagnosis without a prostate cancer mortality benefit (5). Further, as prostate cancer typically grows slowly and the use of the PSA test is common in many countries, it has now become challenging to conduct prospective randomized PSA screening trials based on the need to include hundreds of thousands of men to gain the necessary statistical power. This would make such a trial costly, while still running the risk of the trial being underpowered to detect a significant difference in prostate cancer mortality between trial arms because of higher than anticipated contamination from PSA testing in the control arm. In fact, this was the unfortunate fate of the US Prostate, Lung, Colorectal and Ovarian Cancer screening trial in which >90% of men in both trial arms had a PSA test during the trial period. Therefore, guideline groups need to critically assess the strengths vs weaknesses of prospective randomized trial data and be open to include data from carefully controlled observational studies and sophisticated modeling studies when they evaluate the benefits and risks of various PSA screening strategies. In particular, the balance between benefits vs risks is highly dependent on how and when PSA screening is implemented. Recent data suggest that PSA screening should not follow a one-size-fits-all recipe; examples of such rigid guidelines are systematic PSA testing of men at a certain age (e.g., 55–69 years), the same screening interval for everyone (e.g., every 1, 2, or 4 years), and with biopsy mandated at a certain cutoff (e.g., when PSA is >3 or 4 ng/mL). Rather, PSA screening should be refined and individualized to better stratify each man's risk of life-threatening prostate cancer. Table 1 outlines an example of one such schema: the guideline in place at Memorial Sloan Kettering Cancer Center (MSKCC) (5), which is similar to the National Comprehensive Cancer Network (NCCN) v.2.2018 guideline (https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf). The main differences between the guidelines are that (a) the NCCN guideline also considers digital rectal examination as part of the screening, whereas MSKCC recommends PSA testing without digital rectal examination; (b) the NCCN guideline is more conservative regarding at what age to stop PSA screening; and (c) the NCCN guideline rescreening intervals are narrower. These guidelines are based on the currently available best evidence from randomized trials, observational studies, and modeling studies on how to maximize benefits (reduce risk of metastasis and mortality) and minimize harm (reduce unnecessary prostate biopsy, overdiagnosis, and side effects from treatment). Early cessation of PSA testing for men at age 60 years with a PSA ≤1 ng/mL is recommended in the MSKCC guideline because these men have a low risk of developing life-threatening prostate cancer (0.2% risk of prostate cancer mortality at age 85 years) and would be subject to substantial risk of overdiagnosis and harm if rescreened (5). Example of a risk-based prostate cancer screening algorithm. Start conversations about PSA testing at age 45 years. Engage in shared decision-making about the benefits and harm. Consider using a decision aid Adapt the rescreening interval to a man's age, general health, and PSA level. If the PSA is ≥1 but <3 ng/mL: return for PSA testing every 2–4 years; If the PSA is <1 ng/mL: return for PSA testing at 6–10 years End PSA testing at … Age 60 years for men with PSA ≤1 ng/mL; Age 70 years, unless a man is very healthy and has a higher than average PSA; Age 75 years for all men Consider biopsy if the PSA ≥3 ng/mL after considering several factors, including Repeating the PSA test (because of natural fluctuations or assay variation); Performing digital rectal examination and workup for benign prostatic disease; Measuring reflex tests that improve the specificity of the total PSA and can reduce the number of men needing to undergo prostate biopsy, such as free-to-total PSA ratio, Prostate Health Index, or 4Kscore (before initial or repeat biopsy decisions) or the urinary PCA3 test (before repeat biopsy) If a man is diagnosed with prostate cancer after PSA testing and biopsy: Consider active surveillance for low-risk disease; Refer men with higher risk disease for curative treatment, preferably to a high-volume hospital Start conversations about PSA testing at age 45 years. Engage in shared decision-making about the benefits and harm. Consider using a decision aid Adapt the rescreening interval to a man's age, general health, and PSA level. If the PSA is ≥1 but <3 ng/mL: return for PSA testing every 2–4 years; If the PSA is <1 ng/mL: return for PSA testing at 6–10 years End PSA testing at … Age 60 years for men with PSA ≤1 ng/mL; Age 70 years, unless a man is very healthy and has a higher than average PSA; Age 75 years for all men Consider biopsy if the PSA ≥3 ng/mL after considering several factors, including Repeating the PSA test (because of natural fluctuations or assay variation); Performing digital rectal examination and workup for benign prostatic disease; Measuring reflex tests that improve the specificity of the total PSA and can reduce the number of men needing to undergo prostate biopsy, such as free-to-total PSA ratio, Prostate Health Index, or 4Kscore (before initial or repeat biopsy decisions) or the urinary PCA3 test (before repeat biopsy) If a man is diagnosed with prostate cancer after PSA testing and biopsy: Consider active surveillance for low-risk disease; Refer men with higher risk disease for curative treatment, preferably to a high-volume hospital Reprinted with permission from Vickers et al. (5). For full details, see https://www.mskcc.org/cancer-care/types/prostate/screening/screening-guidelines-prostate. PCA3 = Prostate Cancer Antigen 3. Example of a risk-based prostate cancer screening algorithm. Start conversations about PSA testing at age 45 years. Engage in shared decision-making about the benefits and harm. Consider using a decision aid Adapt the rescreening interval to a man's age, general health, and PSA level. If the PSA is ≥1 but <3 ng/mL: return for PSA testing every 2–4 years; If the PSA is <1 ng/mL: return for PSA testing at 6–10 years End PSA testing at … Age 60 years for men with PSA ≤1 ng/mL; Age 70 years, unless a man is very healthy and has a higher than average PSA; Age 75 years for all men Consider biopsy if the PSA ≥3 ng/mL after considering several factors, including Repeating the PSA test (because of natural fluctuations or assay variation); Performing digital rectal examination and workup for benign prostatic disease; Measuring reflex tests that improve the specificity of the total PSA and can reduce the number of men needing to undergo prostate biopsy, such as free-to-total PSA ratio, Prostate Health Index, or 4Kscore (before initial or repeat biopsy decisions) or the urinary PCA3 test (before repeat biopsy) If a man is diagnosed with prostate cancer after PSA testing and biopsy: Consider active surveillance for low-risk disease; Refer men with higher risk disease for curative treatment, preferably to a high-volume hospital Start conversations about PSA testing at age 45 years. Engage in shared decision-making about the benefits and harm. Consider using a decision aid Adapt the rescreening interval to a man's age, general health, and PSA level. If the PSA is ≥1 but <3 ng/mL: return for PSA testing every 2–4 years; If the PSA is <1 ng/mL: return for PSA testing at 6–10 years End PSA testing at … Age 60 years for men with PSA ≤1 ng/mL; Age 70 years, unless a man is very healthy and has a higher than average PSA; Age 75 years for all men Consider biopsy if the PSA ≥3 ng/mL after considering several factors, including Repeating the PSA test (because of natural fluctuations or assay variation); Performing digital rectal examination and workup for benign prostatic disease; Measuring reflex tests that improve the specificity of the total PSA and can reduce the number of men needing to undergo prostate biopsy, such as free-to-total PSA ratio, Prostate Health Index, or 4Kscore (before initial or repeat biopsy decisions) or the urinary PCA3 test (before repeat biopsy) If a man is diagnosed with prostate cancer after PSA testing and biopsy: Consider active surveillance for low-risk disease; Refer men with higher risk disease for curative treatment, preferably to a high-volume hospital Reprinted with permission from Vickers et al. (5). For full details, see https://www.mskcc.org/cancer-care/types/prostate/screening/screening-guidelines-prostate. PCA3 = Prostate Cancer Antigen 3. The guidelines also incorporate recommendations to pursue additional risk assessments by, for instance, “reflex testing” blood or urine from men with PSA ≥3.0 ng/mL, as indiscriminate prostate biopsy criteria are associated with both overdiagnosis and significant risks of bleeding, infectious complications, and hospitalization. The discoveries in the laboratory by one of the authors (H.L.) of the enzymatic function of PSA and that PSA occurs in several distinct forms in blood, have subsequently led to the development of so-called reflex markers, including the free-to-total PSA ratio, Prostate Health Index (total PSA, free PSA, and [-2]proPSA), and 4Kscore (total, free, intact PSA and human kallikrein-related peptidase 2 combined with clinical information). Numerous studies have shown that predictive models based on the levels of distinct PSA forms in blood can enhance the specificity of total PSA for high-grade prostate cancer, eliminate many unnecessary biopsies, and reduce the detection of low-risk cancers (6). In summary, the changing trends in the use of the PSA test will be included in medical history books. First, we witnessed an indiscriminate use of PSA testing following its discovery and widespread adoption in the US during the late 1980s and early 1990s that led to a dramatic increase in prostate cancer incidence, mainly clinically localized cancer, and a corresponding decrease in the number of men having advanced metastatic disease at diagnosis. Then, the 2012 USPSTF abandonment of PSA screening made the pendulum swing back in the opposite direction, back to pre-PSA-era levels. The recommendation now is to use the PSA test more selectively and in the context of “shared decision-making.” This is a step in the right direction. However, rather than giving a rather vague, and perhaps perplexing, recommendation to men and physicians to talk about the pros and cons if a man is between 55 and 69 years of age, the optimal equilibrium point for the pendulum, and, one that perfectly balances the benefits and harm is, in our view, to give clear and evidence-based instructions about who, when, and how often to screen. One such approach is outlined by the MSKCC guidelines and follows some simple principles: Start conversations about PSA testing at age 45 years and end at age 70 years for most; screen more often if higher than average risk and less frequently if lower risk; before recommending biopsy, consider using additional biomarkers that improve the specificity of the conventional PSA test and help to identify men with clinically significant cancers; and consider active surveillance for men with low-risk prostate cancer. In conclusion, the old dogmas “screen all” and “screen none” need to be abandoned as we now may enter an era of individualized risk-adapted approaches to screening, biopsy, and treatment. prostate-specific antigen European Randomized Study of Screening for Prostate Cancer United States Preventive Services Task Force Memorial Sloan Kettering Cancer Center National Comprehensive Cancer Network.
Source: Clinical Chemistry
Authors: Sigrid V Carlsson, Hans Lilja
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2901173077