Note: Separate PDQ summaries on Prostate Cancer Prevention, Prostate Cancer Treatment, and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Inadequate Evidence of Benefit Associated With Screening for Prostate Cancer Using Prostate-Specific Antigen (PSA) or Digital Rectal Exam (DRE)
The evidence is insufficient to determine whether screening for prostate cancer with prostate-specific antigen (PSA) or digital rectal exam (DRE) reduces mortality from prostate cancer. Screening tests can detect prostate cancer at an early stage, but it is not clear whether earlier detection and consequent earlier treatment leads to any change in the natural history and outcome of the disease. Observational evidence shows a trend toward lower mortality for prostate cancer in some countries, but the relationship between these trends and intensity of screening is not clear, and associations with screening patterns are inconsistent. The observed trends may be due to screening or to other factors such as improved treatment.[
Magnitude of Effect: Uncertain.
|Study Design: Evidence obtained from randomized trials and from observational and descriptive studies (e.g., international patterns studies, time series).|
|Internal Validity: Fair.|
|External Validity: Poor.|
Based on solid evidence, screening with PSA and/or DRE results in overdiagnosis of prostate cancers and detection of some prostate cancers that would never have caused significant clinical problems. Thus, screening leads to some degree of overtreatment. Based on solid evidence, current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men. The most common of these side effects are erectile dysfunction and urinary incontinence.[
Magnitude of Effect: 20% to 70% of men who had no problems before radical prostatectomy or external-beam radiation therapy will have reduced sexual function and/or urinary problems.[
|Study Design: Evidence obtained from cohort studies, case-control studies, and randomized controlled trials.|
|Internal Validity: Good.|
|External Validity: Good.|
Prostate cancer is the most common cancer diagnosed in North American men, excluding skin cancers. It is estimated that in 2022, approximately 268,490 new cases and 34,500 prostate cancer–related deaths will occur in the United States. Prostate cancer is now the second-leading cause of cancer death in men, exceeded by lung cancer. It accounts for 27% of all male cancers and 11% of male cancer-related deaths.[
Cancer statistics from the American Cancer Society and the National Cancer Institute indicated that between 2011 and 2017 the proportion of disease diagnosed at a locoregional stage was 87%, and the proportion of disease diagnosed as distant disease was 7%.[
The biology and natural history of prostate cancer is not completely understood. Rigorous evaluation of any prostate cancer screening modality is desirable because the natural history of the disease is variable, and appropriate treatment is not clearly defined. Although the prevalence of prostate cancer and preneoplastic lesions found at autopsy steadily increases for each decade of age, most of these lesions remain clinically undetected.[
There is an association between primary tumor volume and local extent of disease, progression, and survival.[
Pathological stage does not always reflect clinical stage and upstaging (owing to extracapsular extension, positive margins, seminal vesicle invasion, or lymph node involvement) occurs frequently. Of the prostate cancers detected by digital rectal exam (DRE) in the pre–prostate-specific antigen screening era, 67% to 88% were at a clinically localized stage (T1–2, NX, M0 [T = tumor size, N = lymph node involvement, and M = metastasis]).[
Prostate cancer is uncommonly seen in men younger than 50 years; the incidence rises rapidly each decade thereafter. The incidence rate is higher in African American men than in White men. From 2013 to 2017, the overall age-adjusted incidence rate was 175.2 per 100,000 for African American men and 102.3 per 100,000 for White men.[
The prostate-specific antigen (PSA) test has been examined in several observational settings for initial diagnosis of disease, as a tool in monitoring for recurrence after initial therapy, and for prognosis of outcomes after therapy. Numerous studies have also assessed its value as a screening intervention for the early detection of prostate cancer. The potential value of the test appears to be its simplicity, objectivity, reproducibility, relative lack of invasiveness, and relatively low cost. PSA testing has increased the detection rate of early-stage cancers, some of which may be curable by local-modality therapies, and others that do not require treatment.[
Randomized Trials of PSA Screening
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial
The PLCO Cancer Screening Trial is a multicenter, randomized, two-armed trial designed to evaluate the effect of screening for prostate, lung, colorectal, and ovarian cancers on disease-specific mortality. From 1993 through 2001, 76,693 men at ten U.S. study centers were randomly assigned to receive annual screening (38,343 subjects) or usual care (38,350 control subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal exam (DRE) for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. [
In the screening group, rates of compliance were 85% for PSA testing and 86% for DRE. Self-reported rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41% to 46% for DRE.[
After 7 years of follow-up, with vital status known for 98% of men, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16–1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (ratio rate, 1.13; 95% CI, 0.75–1.70). The data at 10 years were 67% complete and consistent with these overall findings (incidence ratio rate, 1.17; 95% CI, 1.11–1.22 and mortality ratio rate, 1.11; 95% CI, 0.83–1.50). Thus, after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.[
Prostate cancer mortality data after 13 years of follow-up continued to show no reduction in mortality resulting from prostate cancer screening with PSA and DRE.[
There were no apparent associations with age, baseline comorbidity, or PSA testing before the trial, as hypothesized in an intervening analysis by a subgroup analysis. These results are consistent with the previous report at 7 to 10 years of follow-up described above.[
The 13-year follow-up analysis reported 45% of men in the PLCO trial had at least one PSA test in the 3 years before randomization. Annual PSA screening in the usual care arm was estimated to be as high as 52% by the end of the screening period. The intensity of PSA screening in the usual care group was estimated to be one-half of that in the intervention group. Stage-specific treatment between the two arms was similar.[
An extended follow-up analysis for mortality, with median follow-up of almost 17 years (intervention group, 16.9 years; usual-care group, 16.7 years), showed prostate cancer mortality rates of 5.5 (333 deaths) per 10,000 person-years in the intervention group and 5.9 (352 deaths) per 10,000 person-years in the usual-care group, producing a rate ratio of 0.93 (95% CI, 0.81–1.08).[
Possible explanations for the lack of a significant reduction in mortality in this trial include the following:[
The European Randomized Study of Screening for Prostate Cancer (ERSPC)
The ERSPC was initiated in the early 1990s to evaluate the effect of screening with PSA testing on death rates from prostate cancer. Through registries in seven European countries, investigators identified 182,000 men between the ages of 50 and 74 years for inclusion in the study. Although the protocols differed considerably among countries, generally the men were randomly assigned to either a group that offered PSA screening at an average of once every 4 years or to a control group that did not receive screening. The predefined core age group for this study included 162,243 men between the ages of 55 years and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and has been reported through 2010.[
The protocol, including recruitment, randomization procedures, and treatment definition and schedule, differed among countries and was developed in accordance with national regulations and standards. In Finland, Sweden, and Italy, the men in the trial were identified from population registries and were randomly assigned to the centers before written informed consent was provided. In the Netherlands, Belgium, Switzerland, and Spain, the target population was also identified from population lists, but when the men were invited to participate in the trial, only those who provided consent were randomly assigned. Randomization was 1:1 in all countries except Finland, in which it was 1:1.5. The definition of a positive test and the testing schedule also varied by country.
In the screening group, 82% of men accepted at least one offer of screening. At a median follow-up of 9 years, there were 5,990 prostate cancers diagnosed in the screening group (a cumulative incidence of 8.2%) and 4,307 prostate cancers in the control group (a cumulative incidence of 4.8%). There were 214 prostate-cancer deaths in the screening group and 326 prostate-cancer deaths in the control group in the core age group (RR, 0.80; 95% CI, 0.67–0.95). The rates of death in the two study groups began to diverge after 7 to 8 years and continued to diverge further over time.[
Overall, PSA-based screening was reported to reduce the rate of death from prostate cancer by about 20% but was associated with a high risk of overdiagnosis.[
Of the seven centers included in the study, two individually reported a significant mortality benefit associated with prostate cancer screening (the Netherlands and Sweden). It is not readily apparent which factors at these two centers (PSA thresholds or intervals between testing used, mean age of patients, sample size) might explain the observed difference. It is important to note that the trial was not designed for individual countries to have adequate statistical power to find a significant mortality reduction.
Important information that was not reported included the contamination rate in the entire control group. Further, there was some evidence that the treatment administered to the prostate cancer patients differed by stage and by randomly assigned group, with the screening group receiving radical prostatectomy (40.3%) more often than the control group (30.3%). Such a difference in treatment could have contributed to any mortality difference between the trial arms. To address this issue, an analysis was conducted for each treatment, separately in each trial arm, in which logistic regression models were fitted for treatment allocation and risk of prostate cancer death, then combined to estimate prostate cancer deaths. The differences in prostate cancer deaths when the screened arm model was applied to the control arm, and vice versa, were very small, leading the authors to conclude that differential treatment explains only a trivial proportion of the main trial findings.[
However, concerns with this analysis include the following:
The majority of these cases were early stage, including overdiagnosed cases, for which treatment differences would likely make little difference, and from which only a limited fraction of the prostate cancer deaths arise. Thus, any treatment difference effect on the advanced cases, and deaths, would likely be diluted by using this approach.
Possible harms included overdiagnosis, which was estimated at 30% in the Finnish center on the basis of excess cases in the screening arm if the cumulative risk of prostate cancer had been the same as the control arm.[
The Goteborg (Sweden) trial
In December 1994, 20,000 men born between 1930 and 1944 (aged 50–64 years) and living in Goteborg, Sweden, were randomly assigned in a 1:1 allocation to either a control group or a screened group and offered PSA testing every 2 years. The PSA threshold for biopsy was 2.5 ng/mL. Seventy-seven percent of men in the screened group attended at least one screen. At 18 years of follow-up, 1,396 men in the screened group and 962 in the control group had been diagnosed with prostate cancer (hazard ratio, 1.51; 95% CI, 1.39–1.64). There was an absolute reduction in prostate cancer mortality of 0.52% (95% CI, 0.17%–0.87%), with an RR of 0.65 (95% CI, 0.49–0.87).[
A concern with this trial is double reporting of information, because most participants were included in the ERSPC trial, but results have been reported separately for each trial. An initial publication indicated that in 1996 this study became associated with the ERSPC trial, and results from men born between 1930 and 1939 were published in a previous ERSPC report.[
Unlike the other ERSPC centers, not all the participants from the Goteborg center were included in the ERSPC study. Some have argued that the ERSPC trial should be treated as a meta-analysis.[
The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP)
The CAP trial of PSA screening was conducted in the United Kingdom.[
Nine hundred-eleven primary care practices were randomly assigned within 99 geographical areas in the United Kingdom; 466 were assigned to the intervention group, and 445 were assigned to the control group. After various exclusions among both practices and potential participants, the analyses were conducted using data from 189,386 men in 271 practices in the intervention group and 219,439 men in 302 practices in the control group. In the intervention group, 75,707 (40%) men attended a PSA testing clinic, and 67,313 (36%) men had a PSA blood sample taken. Among these men, 11% of men had a PSA level between 3 ng/mL and 19.9 ng/mL (eligible for the ProtecT trial); of whom, 85% of men had a prostate biopsy. Cumulative contamination in the control group was estimated to be 10% to 15% over 10 years.
After a median 10-year follow-up, there was no significant difference between the two groups in prostate cancer mortality. The prostate cancer death rates were 0.30 per 1,000 person-years (549 deaths) in the intervention group and 0.31 per 1,000 person-years (647 deaths) in the control group (rate difference, -0.013 per 1,000 person years [95% CI, -0.047 to 0.022]; RR, 0.96 [95% CI, 0.85–1.08]). Secondary analyses indicated no effect on all-cause mortality (RR, 0.99; 95% CI, 0.94–1.03), but there was a higher prostate cancer incidence rate in the intervention group (4.45 per 1,000 person-years) compared with the control group (3.80 per 1,000 person-years). There was no reduction in advanced prostate cancers (Gleason 8–10 or T4, N1, or M1). The increased detection was confined to lower Gleason grade or lower-stage cancers, emerged at the beginning of screening, and persisted throughout the duration of follow-up, suggesting overdiagnosis.
Limitations of the CAP trial include the following:[
The Norrkoping (Sweden) study
The Norrkoping study is a population-based nonrandomized trial of prostate cancer screening. All men aged 50 to 69 years living in Norrkoping, Sweden, in 1987 were allocated to either an invited group (every sixth man allocated to invited group) or a not-invited group. The 1,494 men in the invited group were offered screening every 3 years from 1987 to 1996. The first two rounds were by DRE; the last two rounds were by both DRE and PSA. About 85% of men in the invited group attended at least one screening; contamination by screening in the not-invited group (n = 7,532) was thought to be low. After 20 years of follow-up, the invited group had a 46% relative increase in prostate cancer diagnosis. Over the period of the study, 30 men (2%) in the invited group died of prostate cancer, compared with 130 (1.7%) men in the not-invited group. The RR of prostate cancer mortality was 1.16 (95% CI, 0.78–1.73).[
The Quebec (Canada) trial
In the randomized prospective Quebec study, 46,486 men identified from the electoral rolls of Quebec City, Canada, and its metropolitan area were randomly assigned to be either approached or not approached for PSA and DRE screening. A total of 31,133 men were randomly assigned to screening, while a total of 15,353 were randomly assigned to observation. Using an intention-to-treat analysis based on the study arm to which an individual was originally assigned, no difference in mortality was seen; there were 75 (0.49%) deaths among the 15,353 men who were randomly assigned to observation group compared with 153 (0.49%) deaths among the 31,133 men randomly assigned to screening group (RR, 1.085).[
The Stockholm (Sweden) trial
In 1988, from a population of 27,464 men in the southern part of Stockholm, 2,400 men aged 55 to 70 years were randomly selected to undergo screening with DRE, transrectal ultrasound, and PSA (cutoff >10 ng/mL). Seventy-four percent of the men accepted the screening invitation. After 20 years of follow-up, there was no indication of a reduction in prostate cancer mortality (RR,1.05; 95% CI, 0.83–1.27) or in overall mortality (RR, 1.01; 95% CI, 0.95–1.06), but screening was limited to a single episode. There was an indication of excess prostate cancer incidence in the invited population (RR, 1.12; 95% CI, 0.99–1.25), suggesting overdiagnosis.[
The authors of a large, randomized, Swedish-based noninferiority trial that was designed to study the performance of magnetic resonance imaging (MRI) in prostate cancer screenings of general populations reported that MRI-targeted biopsy was noninferior to standard biopsy in detecting clinically significant cancers in men with elevated PSA levels. The authors also reported that MRI-targeted biopsy decreased unnecessary biopsies and diagnosis of clinically insignificant cancers. In this prospective, population-based, noninferiority trial, 1,532 men with a PSA level more than 3 ng/mL were randomly assigned in a 2:3 ratio; 603 underwent standard biopsy, and 929 underwent targeted and standard biopsy if MRI findings were concerning for prostate cancer. The primary outcome was the probability of detecting clinically significant cancer (Gleason score of >3+4). The key secondary outcome was the detection of clinically insignificant cancers (Gleason score of <6) and the number of biopsies.[
Key findings of the intention-to-treat analysis included the following:
In summary, initial results of this large randomized trial suggest that men older than 50 years with elevated PSA levels and negative MRI-targeted biopsy may be able to reduce overdiagnosis and overtreatment of low-risk cancer while maintaining the ability to detect clinically significant cancer. Study limitations included low uptake (26% of invited men participated in the trial). Additionally, some participants did not undergo the assigned intervention, and the true disease status of participants was unknown. Another challenge was implementing high-quality MRI screening because of variability of skill and experience among participating radiologists.
Post hoc analysis of randomized screening trials
The problems associated with drawing valid inferences from observational studies also apply to post hoc analyses of randomized trials. For example, analyzing randomized trial results in various ways is subject to the problem association caused by multiplicities. Statistical conclusions maintain their standard interpretations only when analyzing the trial's primary end point according to the trial's protocol or statistical analysis plan. In some settings, statistical adjustments are possible to account for multiplicities. But quite beyond problems of multiplicities, some analyses are so prone to bias that they are of limited value.
Randomization eliminates or at least minimizes many systematic biases. However, randomization shields an analysis from bias only if it considers a group randomized to one intervention compared with a second group randomized to another intervention. If an analysis mixes the two groups, then the virtue of randomization is lost.
Patients can deviate from the intervention to which they were assigned. This is sometimes called contamination. But to preserve the protection of randomization, they are counted within the group to which they were assigned: termed an intention-to-treat or intention-to-screen analysis. An alternative that is sometimes used is an as-treated or as-screened analysis, which is prone to important biases. In such analyses, participants who are actually screened are compared with those who were not screened, regardless of their assigned group. This is attractive to some investigators because it seems to address the right question. In addition, it seems to correct for contamination in both directions, and thereby, increases statistical power; but, such an approach is flawed.
There are powerful biases associated with as-screened analyses; some are easily recognized, and some are not. A participant who chooses to be screened despite randomization to the control group differs from one who accepts an assignment to be screened. For example, such a person may be generally in better health or may have been screened previously, and so, is less likely to be diagnosed with cancer. There are similar differences for participants who eschew invitations to be screened versus those who accept assignment to the control group.
In addition to preserving randomization, an intention-to-screen analysis is most relevant for informing a decision about instituting a screening program or recommendation in some populations. The following section considers two analyses that are subject to the as-screened flaw.
The Quebec study
As indicated above, the intention-to-screen analysis of this trial showed no detectable difference in prostate cancer mortality between the two groups. However, the investigators focused on as-screened analyses. They observed that there were 4 prostate cancer deaths (0.056%) among the 7,155 men who were screened and 44 prostate cancer deaths (0.31%) among the 14,255 men who were not screened, an RR of 5.5. Based on exposure times, the investigators attributed the 67.1% reduction in prostate cancer death rate to screening.[
Modeling the ERSPC combined with the PLCO Cancer Screening Trial
The PLCO cancer screening trial evinced greater contamination than did the ERSPC trials, especially in the control group. Three modeling groups attempted to account for the effect of differential contamination using a novel derived measure called mean lead time (MLT), which reflected the average intensity of screening in each arm in the two trials. The investigators found substantial reductions in prostate cancer mortality caused by screening. Moreover, they found very similar reductions per MLT in PLCO and ERSPC.[
Needle biopsy is the most common method used to diagnose prostate cancer. Most urologists perform a transrectal biopsy using a bioptic gun with ultrasound guidance. Less frequently, a transperineal ultrasound-guided approach can be used for patients who may be at increased risk of complications from a transrectal approach.[
Whether and how magnetic resonance imaging (MRI)−directed biopsy should be incorporated into the diagnostic evaluation of prostate cancer is also under evaluation, either as a replacement of, or in addition to, standard systematic prostate needle biopsies. A multiparametric MRI is performed initially to identify and localize abnormalities that are likely to represent clinically significant prostate cancer. The MRI results are summarized using the 5-point Prostate Imaging–Reporting and Data System (PI-RADS) classification scheme, with 1 being very low likelihood and 5 being very high likelihood of clinically significant prostate cancer.[
The data on MRI-guided biopsy have been reported primarily by experienced MRI radiologists and urologists in referral centers, and generalizability of results is uncertain. A multicenter trial randomly assigned 500 men with clinical suspicion of prostate cancer to either a systematic biopsy or MRI arm. For the latter, men received MRI and received subsequent MRI-guided biopsy if the MRI was suggestive of prostate cancer. There were more men with a Gleason score of 7 or less (95 vs. 64) and fewer men with a Gleason score of less than 7 (23 vs. 55) in the MRI group compared with the systematic biopsy group, with fewer biopsies overall in the MRI group.[
A large, single-arm, single-center study of 2,103 men with MRI-visible lesions who underwent both MRI-directed biopsies and standard systematic prostate needle biopsies under ultrasound visualization showed that MRI-directed biopsy alone detected more clinically significant (Gleason score of 4+3 or higher) disease than did systematic biopsy alone.[
A Swedish noninferiority trial randomly assigned 1,532 men with PSA levels more than 3 ng/mL to a standard-biopsy group (n = 603) versus experimental-biopsy group (n = 929).[
A number of blood- or urine-based markers have been developed to triage men with elevated PSA, especially those with PSA levels ranging from 4 ng/mL to 10 ng/mL. These men should receive biopsy or MRI. Some of these markers have been combined into predictive scores, including the 4K Score, the Prostate Health Index Score, and the Mi Prostate Score.[
Prophylactic antibiotics, especially fluoroquinolones, are often used before transrectal needle biopsies. There are reports of increasing rates of sepsis, particularly with fluoroquinolone-resistant Escherichia coli, and hospitalization after the procedure.[
Because the efficacy of screening depends on the effectiveness of management of screen-detected lesions, studies of treatment efficacy in early-stage disease are relevant to the issue of screening. Treatment options for early-stage disease include radical prostatectomy, definitive radiation therapy, and active surveillance (no immediate treatment until indications of progression are present, but treatment is not designed with curative intent). Multiple series from various years and institutions have reported the outcomes of patients with localized prostate cancer who received no treatment but were followed with surveillance alone. Outcomes have also been reported for active treatments, but valid comparisons of efficacy between surgery, radiation, and watchful waiting are seldom possible because of differences in reporting and selection factors in the various reported series.
A randomized trial in Scandinavian men published in 2002 explored the benefit of radical prostatectomy over watchful waiting in men with newly diagnosed, well-differentiated, or moderately well-differentiated prostate cancers of clinical stages T1b, T1c, or T2.[
A Swedish retrospective study of a nationwide cohort of patients with localized prostate cancer aged 70 years or younger reported that 10-year prostate cancer-specific mortality was 2.4% among men diagnosed with clinically local stage T1a, T1b, or T1c, with a serum PSA of less than 10 ng/mL, and with a Gleason score of 2 to 6, referred to as low-risk cases, of which there were 2,686.[
The Prostate Intervention Versus Observation Trial (PIVOT) was the first trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting.[
A second trial done in the PSA screening era, the Prostate Testing for Cancer and Treatment (ProtecT) study,[
The results suggest that radical treatment has no effect on mortality, although the power to see cause-specific mortality effects was low. Avoidance of metastases or progression could be a rationale for more aggressive treatment, although another study [
In a substudy of ProtecT that examined patient-reported outcomes, the response rate was over 85% for most of the questionnaires used to examine quality of life. The study addressed urinary, bowel, and sexual function, and specific effects of treatment on quality of life, anxiety and depression, and general health. No methods were employed to deal with nonresponse or missing responses. In a quality-of-life study, nonresponse tends to be informative, so this is unusual.[
Results showed that men who had undergone prostatectomy reported more impotence and incontinence; men who received radiation therapy reported more bowel dysfunction; and men who received active monitoring reported the lowest levels of these adverse effects. In general, differences decreased over the 6 years that data were collected. Overall, mental and physical health did not differ by treatment.[
Various methods to improve prostate-specific antigen (PSA) testing in early cancer detection have been developed (see below). The proportion of men who have abnormal PSA test results that revert to normal after 1 year is high (65%–83%, depending on the method).[
Complexed PSA and Percent-Free PSA
Serum PSA exists in both free form and complexed to a number of protease inhibitors, especially alpha-1-antichymotrypsin. Assays for total PSA measure both free and complexed forms. Assays for free PSA are available. Complexed PSA can be found by subtracting free PSA from the total PSA. Several studies have addressed whether complexed PSA or percent-free PSA (ratio of free to total) are more sensitive and specific than total PSA. One retrospective study evaluated total PSA, free/total, and complexed PSA in a group of 300 men, 75 of whom had prostate cancer. Large values of total, small values of free/total, and large values of complexed PSA were associated with the presence of cancer; the authors chose the cutoff of each measure to yield 95% sensitivity and found estimated specificities of 21.8% in total PSA, 15.6% in free/total PSA, and 26.7% in complexed PSA.[
A number of authors have considered whether complexed PSA or percent-free PSA in conjunction with total PSA can improve total PSA sensitivity. Of special interest is the gray zone of total PSA, the range from 2.5 ng/mL to 4.0 ng/mL. A meta-analysis of 18 studies addressed the added diagnostic benefit of percent-free PSA. There was no uniformity of cutoff among these studies. For cutoffs ranging from 8% to 25% (free/total), results ranged from about 45% sensitivity/95% specificity to 95% sensitivity/15% specificity.[
Percent-free PSA may be related to biological activity of the tumor. One study compared the percent-free PSA with the pathological features of prostate cancer among 108 men with clinically localized disease who ultimately underwent radical prostatectomy. Lower percent-free PSA values were associated with higher risk of extracapsular disease and greater capsular volume.[
The third-generation (ultrasensitive) PSA test is an enzyme immunometric assay intended strictly (or solely) as an aid in the management of patients with prostate cancer. The clinical usefulness of this assay as a diagnostic or screening test is unproven.[
Many series have noted that PSA levels increase with age, such that men without prostate cancer will have higher PSA values as they grow older. One study examined the impact of the use of age-adjusted PSA values during screening and estimated that it would reduce the false-positive screenings by 27% and overdiagnosis by more than 33%, while retaining 95% of any survival advantage gained by early diagnosis.[
A number of studies have examined the potential added value of PSA velocity (change over time) for the detection of prostate cancer with mixed results. In a definitive analysis of the Prostate Cancer Prevention Trial (PCPT) data, in which full ascertainment was attempted, regardless of PSA value, PSA velocity added no independent value to the prediction of prostate cancer after adjustment for family history, age, race and ethnicity, PSA, and history of prostate biopsy. For this reason, in the PCPT risk calculator, PSA velocity is not an included variable.[
Alteration of PSA Cutoff Level
A number of authors have explored the possibility of using PSA levels lower than 4.0 ng/mL as the upper limit of normal for screening examinations. One study screened 14,209 White and 1,004 African American men for prostate cancer using an upper limit of normal of 2.5 ng/mL for PSA. A major confounding factor of this study was that only 40% of those men in whom a prostate biopsy was recommended actually underwent biopsy. Nevertheless, 27% of all men undergoing biopsy were found to have prostate cancer.[
Another study adopted a change in the PSA cutoff to a level of 3.0 ng/mL to study the impact of this change in 243 men with PSA levels between 3.0 ng/mL and 4.0 ng/mL. Thirty-two of the men (13.2%) were ultimately found to have prostate cancer. An analysis of radical prostatectomy specimens from this series found a mean tumor volume of 1.8 mL (range, 0.6–4.4). The extent of disease was significant in a number of cases, with positive margins in five cases and pathological pT3 disease in six cases.[
While digital rectal exam has been a staple of medical practice for many decades, prostate-specific antigen (PSA) did not come into common use until the late 1980s for the early diagnosis of prostate cancer. Following widespread dissemination of PSA testing, incidence rates rose abruptly. In a study of Medicare beneficiaries, a first-time PSA test was associated with a 4.7% likelihood of a prostate cancer diagnosis within 3 months. Subsequent tests were associated with statistically significant lower rates of prostate cancer diagnosis.[
In an examination of trends in prostate cancer detection and diagnosis among 140,936 White and 15,662 African American men diagnosed with prostate cancer between 1973 and 1994 in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, substantial changes were found beginning in the late 1980s as use of PSA diffused through the United States; age at diagnosis fell, stage of disease at diagnosis decreased, and most tumors were noted to be moderately differentiated. For African American men, however, a larger proportion of tumors were poorly differentiated.[
Because the outset of PSA screening beginning around 1988, incidence rates initially rose dramatically and fell, presumably as the fraction of the population undergoing their first PSA screening initially rose and subsequently fell. There has also been an observed decrease in mortality rates. In Olmsted County, Minnesota, age-adjusted prostate cancer mortality rates increased from 25.8 per 100,000 men from 1980 to 1984 to a peak of 34 per 100,000 from 1989 to 1992; rates subsequently decreased to 19.4 per 100,000 from 1993 to 1997.[
Cause-of-death misclassification has also been studied as a possible explanation for changes in prostate cancer mortality. A relatively fixed rate was found at which individuals who had been diagnosed with prostate cancer were mislabeled as having died from prostate cancer. As such, the substantial increase in prostate cancer diagnoses in the late 1980s and early 1990s would then explain the increased rate of prostate cancer death during those years. As the rate of prostate cancer diagnosis fell in the early 1990s, this reduced rate of mislabeling death due to prostate cancer would fall, as would the overall rate of prostate cancer death.[
The incidence of distant-stage prostate carcinoma was relatively flat until 1991 and then started declining rapidly. This decline probably was caused by the shift to earlier stage disease associated with the rapid dissemination of PSA screening. This stage shift can have a fairly sizable and rapid impact on population mortality, but it is possible that other factors such as hormonal therapy are responsible for much of the decline in mortality. Ongoing randomized clinical trials in the United States and Europe are designed to determine whether a mortality benefit is associated with PSA screening.[
The Gleason score is an important prognostic measure relying on the pathological assessment of the architectural growth patterns of prostate biopsy. The Gleason grading system assigns a grade to each of the two largest areas of prostate cancer in the tissue samples. A sampling of eight or more biopsy cores improves the pathological grading accuracy.[
As of 2005, approximately 90% of prostate cancers detected were clinically localized and had more favorable tumor characteristics or grades than in the pre-PSA screening era.[
Although digital rectal exam (DRE) has been used for many years, careful evaluation of this modality has yet to take place. The examination is inexpensive, relatively noninvasive, and nonmorbid and can be taught to nonprofessional health workers; however, its effectiveness depends on the skill and experience of the examiner. The possible contribution of routine annual screening by rectal examination in reducing prostate cancer mortality remains to be determined.
Several observational studies have examined process measures such as sensitivity and case-survival data, but without appropriate controls and with no adjustment for lead-time and length biases.[
In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up.[
Since PSA assays became widely available in the late 1980s, DRE alone is rarely discussed as a screening modality. A number of studies have found that DRE has a poor predictive value for prostate cancer if PSA is at very low levels. In the European Study on Screening for Prostate Cancer, it was found that if DRE is used only for a PSA higher than 1.5 ng/mL (thus, no DRE is performed with PSA <1.5 ng/mL), 29% of all biopsies would be eliminated while maintaining a 95% prostate cancer detection sensitivity. By applying DRE only for patients with a PSA higher than 2.0 ng/mL, the biopsy rate would decrease by 36%, while sensitivity would drop to only 92%.[
The PCA3 gene assay was approved by the U.S. Food and Drug Administration in early 2012, with the intended use to aid in the decision for repeat biopsy in men with a previous negative biopsy for an elevated prostate-specific antigen and for whom a repeat biopsy is being considered for a persistently elevated PSA. This test is performed on a urine sample collected after an attentive digital rectal exam (several strokes applied firmly to the prostate to the right and left prostatic lobes). Using a threshold value of 60, this test enhances the detection of prostate cancer while reducing the number of biopsies in men who are expected to ultimately have a negative biopsy.[
The optimal frequency and age range for prostate-specific antigen (PSA) (and digital rectal exam) testing are unknown.[
A report from the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial demonstrated that while more frequent screenings lead to more diagnosed cancers, the detection rate reported for aggressive interval cancers was very similar in the two countries despite their use of different screening frequencies (0.11 with a 4-year interval in Rotterdam and 0.12 with a 2-year interval in Gothenburg). The report suggests that mortality outcomes from the ERSPC (2- and 4-year intervals) and PLCO (1-year interval relative to opportunistic screening) trials should facilitate a more reliable assessment of the benefits and costs of different screening intervals.[
Of serious concern with regard to prostate cancer screening is the high prevalence of histologically defined cancer. It has been demonstrated that a considerable fraction (approximately one-third) of men in their fourth and fifth decades have histologically evident prostate cancer.[
Prostate biopsies in a small percentage of men will demonstrate prostatic intraepithelial neoplasia (PIN). High-grade PIN is not cancer but may predict an increased risk of prostate cancer. PSA does not appear to be elevated with PIN.[
A number of computer simulation models have been developed to analyze trends in prostate cancer detection. The models were also developed to compare these trends with the reported decrease in prostate cancer deaths observed in the United States since the early 1990s, to investigate the cost-effectiveness of various screening strategies, and to attempt to estimate overdiagnosis resulting from screening.
One of the first models looked at trends in prostate cancer detection compared with prostate cancer deaths between 1992 and 1994. Changes in prostate cancer mortality could not be explained entirely by prostate-specific antigen (PSA) screening alone.[
An example of the underlying assumptions and concerns about models is provided by a microsimulation modeling effort that examined the comparative effectiveness of 35 screening strategies, which varied by start and stop ages, screening intervals, and thresholds for biopsy referral.[
While awaiting results of current studies, physicians and men (and their partners) are faced with the dilemma of whether to recommend or request a screening test. A qualitative study undertaken on focus groups of men, physician experts, and couples with screened and unscreened men has explored types of information that may help inform a man making a decision regarding prostate-specific antigen screening.[
Screening increases the detection of indolent, unsuspected, and asymptomatic prostate cancer. Any potential benefits derived from screening asymptomatic men need to be weighed against the harms of screening and diagnostic procedures and treatments for prostate cancer. These harms are particularly burdensome to men with false-positive screening results and men who are unnecessarily treated because of overdiagnosis.
An unintended consequence of screening and biopsy is the erroneous assumption that a screened population is at increased risk of developing significant disease. In a study that examined the magnitude of prostate cancer risk associated with specific factors across the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and Prostate Cancer Prevention Trial cohorts, the authors demonstrated that the likelihood of undergoing screening and biopsy depends on certain known or suspected risk factors. In turn, differential screening and biopsy can result in spurious conclusions regarding risk factors for prostate cancer.[
Negative impacts of screen detection on measures of risk may include the following:
Measurements of risk in men who undergo screening differ from measurements of risk in men who do not undergo screening. Past and current screening and biopsy practices may misrepresent prostate cancer risk factors. Better methods for identifying consequential prostate cancer are needed to avoid unnecessary biopsies.[
Three cohort studies in Sweden and the United States linked databases to examine the association between a new diagnosis of prostate cancer and cardiovascular events/death or suicide. One Swedish study found that in the first year after a diagnosis of prostate cancer, the risk of death from cardiovascular disease (CVD) was increased in men diagnosed with prostate cancer compared with men who were not diagnosed with prostate cancer (relative risk [RR], 1.9; 95% confidence interval [CI], 1.9–2.0; adjusted for age, calendar time period, and time since diagnosis). The risk of death from CVD was highest in the first week after diagnosis (RR, 11.2; 95% CI, 10.4–12.1) and was also higher in younger men (age <54 years). These risks were lower in men diagnosed in the most recent time periods. Also, in the first year after diagnosis, the risk of committing suicide was higher for men who had been diagnosed with prostate cancer (RR, 2.6; 95% CI, 2.1–3.0; adjusted for age, calendar time period, marital status, educational level, and history of psychiatric hospitalization). Again, this was highest in the first week after diagnosis (RR, 8.4; 95% CI, 1.9–22.7).[
A U.S. cohort study explored the association between prostate cancer diagnosis and CVD mortality or suicide in men diagnosed with prostate cancer, compared with population-level expected rates during three different time periods (preprostate-specific antigen [pre-PSA], peri-PSA, and post-PSA). For CVD mortality, the standardized mortality ratio (SMR) was elevated for men diagnosed with prostate cancer in the first month after diagnosis in all time periods (overall SMR, 2.05; 95% CI, 1.89–2.22), but decreased in later months during the first year (decreasing to <1.0 in the PSA time period). This association was not changed significantly by age, race, or tumor grade. SMRs were higher for nonmarried men, for men who lived in lower educational status or higher poverty counties, and for men with metastatic disease at diagnosis. Also, in the first 3 months after diagnosis, the SMR for suicide was higher in men with prostate cancer (SMR, 1.9; 95% CI, 1.4–2.6). In months 4 to 12, the SMR was lower but still greater than 1.0. The SMR for suicide, however, was greater than 1.0 only in the pre-PSA and peri-PSA time periods, but not in the post-PSA time period. SMR was higher for nonmarried men but did not vary by education or poverty.[
These data lend credence to the concern that overdiagnosis of prostate cancer due to screening could lead to an increased risk of CVD mortality or suicide.
Although there is no literature suggesting serious complications of digital rectal examination (DRE) or transrectal sonography, and the harms associated with venipuncture for PSA testing can be regarded as trivial, prostatic biopsies are associated with important complications. Transient fever, pain, hematospermia, and hematuria are all common, as are positive urine cultures.[
Long-term complications of radical prostatectomy include urinary incontinence, urethral stricture, erectile dysfunction, and the morbidity associated with general anesthesia and a major surgical procedure. Fecal incontinence can also occur. The associated mortality rate is reported to be 0.1% to 1%, depending on age. In the population-based Prostate Cancer Outcomes Study, 8.4% of 1,291 men were incontinent and 59.9% were impotent at 18 or 24 months following radical prostatectomy. More than 40% of men reported that their sexual performance was a moderate-to-large problem. Both sexual and urinary function varied by age, with younger men relatively less affected.[
Definitive external-beam radiation therapy can result in acute cystitis, proctitis, and sometimes enteritis. These conditions are generally reversible but may be chronic. In the short-term, potency is preserved with irradiation in most cases but may diminish over time. A systematic review of evidence radiation therapy complications shows that 20% to 40% of men who had no erectile dysfunction before treatment developed dysfunction 12 to 24 months afterward. Furthermore, 2% to 16% of men who had no urinary incontinence before treatment developed dysfunction 12 to 24 months afterward, and about 18% of men had some bowel dysfunction 1 year after treatment. The magnitude of effects of brachytherapy has not been determined, but the spectrum of complications are similar.[
The question of whether prostate cancer treatment contributes to symptoms among screened prostate cancer survivors was addressed in an analysis from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The randomized controlled PLCO analysis compared 529 prostate cancer survivors, 5 to 10 years postdiagnosis, with 514 noncancer controls, regarding prostate cancer-specific symptomatology. There was poorer sexual and urinary function among prostate cancer survivors compared with noncancer controls, suggesting that these symptoms are related to prostate cancer treatment, not aging or comorbidities.[
Screening has increased the incidence of prostate cancer. In the current medical climate, most early-stage prostate cancers are treated by radical surgery or irradiation with intent to eradicate the pathology. There is evidence that not all patients diagnosed with prostate cancer as a consequence of screening are in immediate need of curative treatment. Death from other causes often occurs before screen detected, localized, and well-differentiated malignancies affect the survival of these patients. To avoid overtreatment and consequent morbid events, active surveillance (AS) is an emerging strategy applicable in these kinds of cases wherein curative treatment is delayed pending objective medical evidence of disease progression.[
The effectiveness of AS was investigated retrospectively in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Data from 577 men diagnosed with prostate cancer as a consequence of periodic screening between 1994 and 2007 at a mean age of 66.3 years in four participating clinical centers in the Netherlands, Sweden, and Finland were evaluated. Selection criteria for inclusion in the analysis were:
Men with positive lymph nodes or distant metastases at the time of diagnosis were excluded from the analysis. These are the same thresholds being applied in the (as yet unreported) prospective Prostate Cancer Research International: Active Surveillance study on AS originating from ERSPC and in the (also unreported) protocol-based prospective study of AS in Canada.
The mean follow-up time for the 577 men in the retrospective assessment was 4.35 years (0–11.63 years). The calculated 10-year prostate cancer-specific survival rate was 100%. The overall 10-year survival rate was 77%. The calculated 10-year deferred treatment-free survival rate was 43%.
After 7.75 years, 50% of men had received treatment. The median treatment-free survival was 2.5 years. Men treated during follow-up were slightly younger at diagnosis than men remaining untreated (64.7 years vs. 67.0 years; P < .001). Of the 110 men shifting to active treatment despite favorable PSA levels and PSA doubling times, DRE was known in 53 of the men and played a role in nine of them, whereas rebiopsies were known in 27 of the men and played a role in none of them. On the basis of PSA characteristics, 1.9% of patients who remained untreated may have been better candidates for active treatment, while 55.8% of men who received active treatment were not obvious candidates for radical treatment, and neither DRE nor rebiopsy explained the discrepancy. Factors like anxiety and urologic complaints may have been more explanatory, but the data were not available.
The authors concluded that their data confirmd previous studies' findings, that many screen-detected prostate cancers may be actively followed (e.g., AS), and curative treatment delayed, thereby delaying or avoiding the morbid consequences of radical therapy without diminishing survival. The authors also noted that a considerable fraction of men do not comply with the AS regimen, apparently for psychological reasons, and AS often resulted in delay, not avoidance, of radical therapy.
In the Prostate Testing for Cancer and Treatment (ProtecT) study, 1,643 men with localized prostate cancer were randomly assigned equally to active monitoring, surgery, or radiation therapy. The primary endpoint was death from prostate cancer, and secondary outcomes were clinical (local) progression, metastases, and death from all causes.[
In a substudy of ProtecT that examined patient-reported outcomes, the response rate was over 85% for most of the questionnaires used to examine quality of life. The study addressed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. No methods were employed to deal with nonresponse or missing responses. In a quality-of-life study, nonresponse tends to be informative, so this lapse is unusual.[
Results showed that men who had undergone prostatectomy reported more impotence and incontinence; men who received radiation reported more bowel dysfunction; and men who received active monitoring reported the lowest levels of these adverse effects. In general, differences decreased over the 6 years that data were collected. Overall, mental and physical health did not differ by treatment.[
Whatever the screening modality, the screening process itself can lead to psychological effects in men who have a prostate biopsy but do not have prostate cancer. One study of these men at 12 months after their negative biopsy who reported worrying that they may develop cancer (P < .001), showed large increases in prostate-cancer worry compared with men with a normal PSA (26% vs. 6%).[
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Incidence and Mortality
Updated statistics with estimated new cases and deaths for 2022 (cited American Cancer Society as reference 1). Also revised text to state that between the mid-1990s and mid-2010s, mortality rates declined by about 50%; however, from 2015 to 2019, mortality rates decreased by 0.6% per year.
Revised text to state that cancer statistics from the American Cancer Society and the National Cancer Institute indicated that between 2011 and 2017 the proportion of disease diagnosed at a locoregional stage was 87%, and the proportion of disease diagnosed as distant disease was 7%.
Screening by Serum Prostate-Specific Antigen (PSA)
Added text to state that the Spanish center of the European Randomized Study of Screening for Prostate Cancer reported an excess of prostate cancers in the intervention arm versus the control arm after a median 21 years of follow-up (cited Luján et al. as reference 15).
Added text to state that the authors of a large, randomized, Swedish-based noninferiority trial that was designed to study the performance of magnetic resonance imaging (MRI) in prostate cancer screenings of general populations reported that MRI-targeted biopsy was noninferior to standard biopsy in detecting clinically significant cancers in men with elevated PSA levels. The authors also reported that MRI-targeted biopsy decreased unnecessary biopsies and diagnosis of clinically insignificant cancers (cited Nordström et al. as reference 23).
Added text to state that the key findings of the intention-to-treat analysis included that clinically significant cancer was diagnosed in 192 of 929 men in the MRI-targeted biopsy group versus 106 of 603 men in the standard-biopsy group; clinically insignificant prostate cancer was diagnosed in 41 men in the MRI-targeted group versus 73 men in the standard-biopsy group; biopsies were benign in 105 men in the MRI-targeted group verus 259 men in the standard-biopsy group; antibiotic-treated postbiopsy infections occurred in 2% of the MRI-targeted group versus 4% of the standard-biopsy group; and when normalized to 10,000 men, MRI-targeted biopsies resulted in 409 fewer men undergoing biopsy, 366 fewer men with benign biopsies, and 88 fewer men with clinically insignificant cancers.
Added text to state that initial results of this large randomized trial suggested that men older than 50 years with elevated PSA levels and negative MRI-targeted biopsy may be able to reduce overdiagnosis and overtreatment of low-risk cancer while maintaining the ability to detect clinically significant cancer.
Prostate Cancer Diagnosis
Added this new section.
This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about prostate cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Prostate Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389383]
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Last Revised: 2022-02-18
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