The 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. 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.[30-33] The possibility of identifying an excessive number of false-positives in the form of benign prostatic lesions requires that the test be evaluated carefully. Furthermore, there is a risk of overdiagnosis and overtreatment (i.e., the detection of a histological malignancy that if left untreated would have had a benign or indolent natural history and would have been of no clinical significance). Randomized trials have therefore been conducted.
Randomized trials of PSA screening
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial
The Prostate, Lung, Colorectal, and Ovarian (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 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. Organized screening in the intervention group of the trial did not produce a mortality reduction compared with opportunistic screening in the usual care group. There were 4,250 men diagnosed with prostate cancer in the intervention group and 3,815 men in the usual care group. Cumulative incidence rates were 108.4 per 10,000 person-years in the intervention group and 97.1 per 10,000 person-years in the usual care group (relative risk [RR], 1.12; 95% CI, 1.07–1.17). The cumulative prostate cancer mortality rates were 3.7 (158 deaths) per 10,000 person-years in the intervention group and 3.4 (145 deaths) per 10,000 person-years in the usual care group (RR, 1.09; 95% CI, 0.87–1.36).
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 update accounts for 76,685 men, aged 55 to 74 years, enrolled at 10 screening centers between November 1993 and July 2001 who were randomly assigned to either annual PSA screening for 6 years and DRE for 4 years (38,340 men) or usual care (38,345 men), which sometimes included opportunistic screening in local communities. All prostate cancer incidents and deaths through 13 years of follow-up or through December 31, 2009 were ascertained.
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. 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 15 years (intervention group, 14.8 years; usual-care group, 14.7 years), showed prostate cancer mortality rates of 47.8 (255 deaths) per 100,000 person-years in the intervention group and 46.0 (244 deaths) per 100,000 person-years in the usual-care group, given a rate ratio of 1.04 (95% CI, 0.87–1.24). An analysis of nonprotocol screening during the postscreening phase of the trial showed that 78.7% of men in the usual-care group and 80.3% of men in the intervention group had received a PSA test within the past 3 years, and that 85.9% of men in the usual-care group and 98.9% of men in the intervention group had ever had a PSA test.
The following are several possible explanations for the lack of a reduction in mortality in this trial:[35,37]
- Annual screening with the PSA test using the standard U.S. threshold of 4 ng per mL and DRE to trigger diagnostic evaluation may not be effective.
- The substantial level of screening in the control group could have diluted any modest effect of annual screening in the intervention group.
- Approximately 44% of the men in each study group had undergone one or more PSA tests at baseline, which would have eliminated some cancers detectable on screening from the randomly assigned population; thus, the cumulative death rate from prostate cancer at 10 years in the two groups combined was 25% lower in those who had undergone two or more PSA tests at baseline than in those who had not been tested.
- Improvement in therapy for prostate cancer during the course of the trial may have resulted in fewer prostate-cancer deaths in the two study groups, which blunted any potential benefits of screening.
- After a PSA finding greater than 4.0 ng/mL, within 1 year only 41% of men underwent prostate biopsy; within 3 years of this finding, only 64% of men underwent prostate biopsy. Such lower biopsy rates, associated with lower prostate cancer detection rates, may have blunted the impact of screening on mortality.
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 were 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 trials 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. With follow-up through 13 years, there were 7,408 prostate cancers in the intervention group during 775,527 person-years of follow-up and 6,107 cancers in the control group with 980,474 person-years of follow-up (RR, 1.57; 95% CI, 1.51–1.62). There were also 355 prostate cancer deaths over 825,018 person-years of follow-up in the intervention group and 545 deaths over 1,011,192 person-years of follow-up in the control group (RR, 0.79; 95% CI, 0.69–0.91). Consequently, 781 men needed to be invited for screening to avert one prostate cancer death, and 48 men needed to be biopsied.
Thus, 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.
Figure 1 shows the risk of prostate cancer death associated with PSA-based screening, compared with controls for up to 13 years of follow-up for each of the study centers in the ERSPC for which data are currently available.[38,39] Of the seven countries included in the study, only two countries reported a mortality benefit associated with prostate cancer screening (the Netherlands and Sweden), and it is not readily apparent which factors at these two sites (e.g., PSA thresholds or intervals between testing used, mean age of patients) might explain the observed difference.
Important information that was not reported includes the contamination rate in the entire control group. There was some evidence that the treatment administered to the prostate cancer cases differed by stage and by randomly assigned group, with the screening group more often receiving radical prostatectomy (40.3%) than the control group (30.3%). However, no analysis of the overall effect of this difference on the mortality outcome has been reported. Incompleteness of data is also a concern because it appears that several of the participating countries have not yet provided data beyond the 10-year point at which the major effect appears to occur. Longer follow-up and further analysis will be needed to determine the final results of this trial.
Possible harms included overdiagnosis, which was estimated at 30% 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) center
The Swedish (Goteborg) center of the ERSPC reported results separately after the initial publication of the overarching ERSPC findings. The Goteborg center randomized approximately 20,000 men born between 1930 and 1944, and data from participants born between 1930 and 1939 (60% of the total) were used in the pooled ERSPC data. With follow-up extended to 18 years in the screening group, 79 men died of prostate cancer (0.98% cumulative mortality) compared with 122 prostate cancer deaths in the control group (1.5% cumulative mortality), a 35% relative reduction. The authors reported that 139 men needed to be invited for screening to avert one prostate cancer death.
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 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). This nonstatistically significant finding provides no evidence that screening leads to a reduction in prostate cancer mortality, even after 20 years of follow-up.
The Quebec (Canada) trial
In the randomized, prospective Quebec study, 46,486 men identified from the electoral rolls of Quebec City 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 compared with 153 (0.49%) deaths among the 31,133 men randomly assigned to screening (RR, 1.085).
Post hoc analysis of randomized screening trials
The problems associated with drawing valid inferences from observational studies also applies 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 with another 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 in regards to 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. This conclusion is flawed, as pointed out by other investigators. (see above)
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 groups. Three modeling groups attempted to account for this discrepancy, while at the same time employing a previously unused as-screened analysis rather than using an intention-to-screen analysis. Using a derived measure called mean lead-time (MLT), the investigators found substantial (likely inflated) reductions in prostate cancer mortality caused by screening. Moreover, they found very similar reductions per MLT in PLCO and ERSPC. Both methods and conclusions are prone to bias conclusions and have been criticized by several groups of scientists.[47,48] This analysis also ignored the other potential shortcomings identified above. (see above)
Of the 2,752 articles retrieved, 68 eligible studies involving 3,029 participants were identified (Fig 1). The characteristics of the studies are provided in Table 1 and S1 Table. Forty studies (59%) included men with and without a history of screening. Nine (13%) studies included men who had not been screened, and 4 (6%) studies included men who had been previously screened. Fifteen (22%) studies did not report participant’s history of screening. Both methods for screening, PSA or DRE, were used, however the number of men that used either method was not reported in most studies. The studies were conducted in nine countries, including the United States (49 [72%]; of which 26 (38%) only included African American men), United Kingdom (7 [10%]), Australia (6 [9%]), Barbados, Belgium, Canada, Germany, Nigeria and Uganda (1 study each).
Comprehensiveness of reporting of included studies
The comprehensiveness of reporting was variable, with studies reporting 7 to 23 of the 25 items in the adapted COREQ checklist (Table 2). The participant selection strategy was described in 58 (85%) studies, and data saturation was reported in 28 (41%) studies. The use of software to facilitate data analysis was reported in 41 (60%) studies, and 52 (76%) reported on the use of researcher triangulation. Almost all studies (66 [97%]) provided participant quotations.
We identified five themes on men’s perspectives on prostate cancer screening: social prompting, gaining decisional confidence, preserving masculinity, avoiding the unknown and uncertainties, and prohibitive costs. The respective subthemes are described below. Table 3 provides selected participant quotations from the included studies, and indicates the studies that contributed to each theme. A thematic schema to illustrate the conceptual links among themes is provided in Fig 2.
Trusting professional opinion–Some participants had “confidence in doctors” to initiate and make recommendations about prostate cancer screening.[19, 27, 28, 38, 47, 49, 52, 54, 59, 60, 78, 81, 83, 91, 93] Many felt overwhelmed by the complicated medical information and thus did not feel competent enough to “evaluate the pros and cons or the risks” on their own.[38, 52] Having a strong relationship with their health care provider allowed participants to make this important health decision for them.
Motivation from family and friends–Family and friends motivated men to be screened for prostate cancer.[40, 41, 47, 55–57, 71, 72, 79, 83, 91, 92, 99] Participants appreciated their spouses’ encouragement, their constant “nagging” to pursue screening and “for sticking by”, during the decision making and screening process. Having a family member who had prostate-related problems (e.g. benign prostatic hyperplasia) also prompted them to undergo screening, as they “wouldn’t have started checking” otherwise.[65, 69, 83, 91, 98]
Proximity and prominence of cancer–Participants who had seen the devastating impact of cancer among their family or friends felt acutely aware of cancer, and were prompted to undergo prostate cancer screening.[21, 42, 47, 51, 60, 65, 66, 69, 75, 83, 85, 91, 100] The death of family members due to cancer and “seeing what [they] went through” as well as understanding the potential of cancer “running in the family,” caused participants to become proactive about cancer screening, including for prostate cancer. Some believed their family members had cancer detected “too late”.
Gaining decisional confidence.
Overcoming fears–Preparing to screen for prostate cancer was described by participants as a “psychological game” that required them to overcome the stigma surrounding the screening procedure.[19, 27, 55, 61, 81, 82] Prostate cancer screening was initially perceived as “embarrassing,” “uncomfortable,” and “dreaded,” which was later on accepted as “necessary,”  and “routine.”
Survival imperative–Improving their chance of survival through early detection motivated men to undergo prostate cancer screening.[20, 21, 28, 36, 42, 43, 60, 71, 74, 77, 85, 91, 92] Early detection was perceived as imperative to prevent severe morbidity or mortality, so they could continue to live a “normal life.” They believed that cancers detected early had a “higher chance” of cure.
Peace of mind–The possibility of prostate cancer was often “constantly nagging at the back of their mind” particularly for men with increased risk due to family history of the cancer. Some participants believed they had “nothing to lose” by going ahead with the screening. By doing so, they felt reassured and their “mind was at ease.”[36, 39, 48, 52, 71, 79, 92] Prostate cancer screening provided “peace of mind for family and loved ones too.”
Mental preparation–Preparing for the procedure of screening was psychologically confronting and overwhelming for men.[19, 49, 79] The fear of having an invasive procedure required men to be mentally prepared as they were hesitant to commit. [19, 79] After the test, many men felt “anxious” awaiting the results and left with a “great void of uncertainty” as they were terrified to receive a positive result.
Prioritising wellbeing–Men valued survival and family: “I want to live as long as I can and be around for my children and grandchildren.” For those who had not experienced severe health problems, they “did not want to run the risk” and instead “wanted to be preventive, instead of regretting” their decision in the future. Some regarded prostate cancer screening as a “win-win situation”, and regardless of the outcome, they could “not go wrong.” Some men strived to maintain a sense of control of their body, and were “curious” and wanted to know “what is really going on in my body”, and thus were inclined to participate in prostate cancer screening.
Bodily invasion–Some men felt a loss of personal dignity after undergoing the invasive procedure of screening.[20, 27, 53, 55, 60, 61, 81, 82, 88, 94, 97, 100] For men who had not previously been screened for prostate cancer they were fearful of the procedure and did not like the idea of a doctor “messing with me there.” For men who had participated they felt the procedure was “violating” and some “felt invaded,”[27, 81, 82, 97] and therefore were unwilling to complete the screening again.[78, 82] Some persevered through the unpleasantness of the procedure by focussing on the necessity–“if I need it I’ll get it done”.
Losing sexuality–Men were fearful that consequences of screening may cause sexual dysfunction,[19, 20, 27, 57, 58, 60, 65, 68, 71–75, 77, 78, 92, 94, 100] and this was a “major concern.” Being unable to perform sexually would be “devastating.” Prostate cancer and subsequent prostatectomy was seen as “taking the manhood away” and thus men were reluctant to undergo screening. They wanted to avoid diagnosis of prostate cancer as they did “not want to end up impotent,” which some had observed in other men who had been treated for prostate cancer.
Threatening manhood–Being diagnosed with prostate cancer was perceived to potentially jeopardise a man’s manhood or masculinity.[19, 39, 41, 42, 51, 53, 55, 57, 60, 63–66, 69, 70, 72, 74, 75, 78, 82, 84, 88, 89, 94, 96, 97] Their “macho man” image would be compromised, as “being unhealthy is a sign of being unmanly.” Some men were uneasy and reluctant to be screened as the DRE was perceived to have “homosexual implications.”[19, 51, 69, 74, 89] Some also feared being diagnosed with prostate cancer as they would have to relinquish their role as “the rock” of their family.
Medical avoidance–Some participants were generally averse to interacting with the medical system, particularly if it was seen as unnecessary given the absence of symptoms or perceptible health problems.[19–21, 27, 28, 37, 42, 45, 53, 55, 63, 64, 69, 72, 86, 88, 89, 92] They reasoned that “if it don’t hurt don’t fix it.” Even after been advised by a doctor to undergo further tests or examinations they would “postpone and postpone” as they refused to be seen as vulnerable and were terrified of potentially receiving bad news. Some men believed that it was “not socially acceptable” to go to the doctor like women,[55, 64, 69, 70, 86] which they attributed to their macho mentality[21, 63, 72]–that they were “tough” and “infallible.”
Avoiding the unknown and uncertainties.
Taboo of cancer-related death–Fears of being potentially diagnosed with prostate cancer and dying caused men to ignore the matter.[19, 20, 28, 36, 37, 39, 41, 42, 54, 56, 62, 63, 77–79, 88, 92, 96, 99, 100] In one study, African American men felt that “anything that a Black man thinks is gonna kill him, he ain’t gonna want to talk about”. Cancer was considered to be “a death sentence,” and men expressed that they would “rather not know”. For men who had previous or ongoing health problems, they were particularly concerned that another diagnosis i.e. of prostate cancer would increase the burden of living with the disease to beyond what they could cope with.
Lacking tangible cause–The absence of signs and symptoms made it difficult for men to understand the value of screening.[20, 36, 43, 50, 58, 62, 64, 69, 74, 84–86, 89, 98] Some felt they were healthy and were convinced that “if it’s not affecting me, why bother with it?” as there was “nothing wrong…no pain or disease.”
Physiological and symptomatic obscurity–Although participants indicated their awareness of prostate cancer, some did not know “what the gland’s there for, we don’t know what it does, so we don’t know what to do.” One participant highlighted that he was “pretty ignorant“ as he “didn’t even know women didn’t get it.” Some younger men felt there was no need to spend time and money for screening as prostate cancer was an “old man” cancer. Further, participants had lack of awareness of the symptoms of prostate cancer.
Ambiguity of the procedure–Some men described having a vague understanding of the procedures of prostate cancer screening, which caused them to feel concerned and anxious about undergoing screening.[36, 42, 54, 65, 88, 91] Screening was at times acted upon because they received instruction by their doctor, although they had little knowledge regarding the PSA testing. Due to lack of knowledge and awareness, some men stated there was “too much confusion” and assumed that all prostate cancer screening was “invasive” and “painful.” However, some became aware that a blood test was available, and were relieved that they would not have to undergo a DRE.
Confusing controversies–The controversies regarding the accuracy of prostate cancer screening caused some men to feel confused and uncertain.[21, 36, 38, 46, 52, 62, 65, 67, 69, 83, 92, 95] They questioned “what’s the point of getting a test if it might not be reliable?” For others, they found the procedure “not that reassuring,” as there was still a chance they could have prostate cancer. Thus, decision making was complex as they had to “evaluate the pros and cons” in the context of such uncertainties. Some men also disclosed that the potential risks involved in prostate cancer screening were not addressed by doctors, despite highlighting the benefits of the procedure. 
The cost of prostate cancer screening created difficulty for men seeking participation[19, 20, 27, 40, 54, 60, 64, 80, 89, 90] as many were not “able to afford the doctors.” However, concerns regarding costs were only identified among African American and African-Caribbean participants in the United States. In 14 studies involving African American men, men disclosed that they could not afford health insurance and therefore were unable to be screened for prostate cancer despite their increased risk.[19, 20, 27, 39, 40, 54, 62, 64, 71, 73, 76, 80, 87, 89] African-Caribbean men also articulated that “health insurance is probably the biggest impediment” for men to regularly partake in screening.