Evidence of Benefit
Before the 1990s, the digital rectal examination (DRE) was the test traditionally used for prostate cancer screening. Two other procedures are also available: transrectal ultrasound (TRUS) imaging and serum prostate-specific antigen (PSA) concentrations. Prostate cancer screening is controversial because of the lack of definitive evidence of benefit. A small randomized trial in Sweden evaluated the effects of screening men aged 50 to 69 years every 3 years; the first two screenings included DRE only, followed by two screenings with DRE combined with a test for PSA. The trial was not powered to detect even moderate differences in prostate cancer mortality, which was the same in the two groups: 1.3% (20 of 1,494 patients) for men assigned to screening and 1.3% (97 of 7,532 patients) for controls. The controversy persists. A nested case-control study was conducted at ten U.S. Department of Veterans Affairs (VA) medical centers in New England (71,661 patients receiving ambulatory care between 1989 and 1990), identifying 501 patients who were diagnosed with adenocarcinoma of the prostate from 1991 to 1995 and who died between 1991 and 1999. Controls were selected from among patients living at the time case patients died (matched 1:1 for age and VA facility). A benefit from screening by PSA or PSA and/or DRE was not found for PSA (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.71–1.64; P = .72) or for PSA and/or DRE (OR, 1.13; 95% CI, 0.63–2.06; P = .68). Because prostate cancer has a relatively slow course, it is possible that the relatively short follow-up period in this study precluded the observation of a benefit, which might accrue only after 10 or more years from the time of screening.
Adding to the controversy is the lack of consensus regarding optimal treatment of localized disease and the clear evidence that active treatment options are associated with significant morbidity. Treatment options for early-stage disease include radical prostatectomy, definitive radiation therapy, and watchful waiting (no immediate treatment; treatment if indications of progression are present, but treatment not designed with curative intent). Multiple series from various years and institutions have been reported on 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. Six hundred ninety-eight men younger than 75 years, most with clinically detected rather than screen-detected cancers (unlike most newly diagnosed patients in North America) were randomly assigned to the two-arm trial. After 5 years of follow-up, the difference in prostate cancer-specific mortality between radical prostatectomy and watchful waiting groups was 2%; after 10 years of follow-up, the difference was 5.3% (relative risk [RR], 0.56 [0.36–0.88]). There was also a difference of about 5% in all-cause mortality that was apparent only after 10 years of follow-up (RR, 0.74 [0.56–0.99]). Thus, to extend one life, 20 men with palpable, clinically localized prostate cancer would need to undergo radical prostatectomy rather than watchful waiting. Because most prostate cancers that are detected today with PSA screening are not palpable, this study may not be directly generalizable to the average newly diagnosed patient in the United States.
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. This subgroup analysis was derived from a cohort study of 6,849 men diagnosed between January 1, 1997 and December 31, 2002, aged 70 years or younger, who had local stage T1 to T2 with no signs of lymph node metastases or bone metastases, and a PSA serum level of less than 20 ng/mL, as was abstracted from the Swedish Cancer Registry, which captured 98% of solid tumors among men aged 75 years or younger. Cohort treatment options were surveillance (n = 2,021) or curative intent by radical prostatectomy (n = 3,399) or radiation therapy (n = 1,429), which were to be determined at the discretion of treating physicians. Surveillance or expectancy treatment was either active surveillance with curative treatment if progression occurred or watchful waiting—a strategy for administering hormonal treatment upon symptomatic progression. Using all-cause mortality as the benchmark, the study calculated cumulative incidence mortality for the three treatment groups of the entire cohort and the low-risk subgroup. Surveillance was more common among men with high comorbidity and among men with low-risk tumors. The 10-year cumulative risk of death from prostate cancer for the entire 6,849 person cohort was 3.6% in the surveillance group and 2.7% in the curative-intent group compared with the low-risk surveillance group (2.4%) and the low-risk curative-intent group (0.7%). Biases inherent in treatment assignment could not be accounted for adequately in the analysis, which prevented conclusions about the relative effectiveness of alternative treatments. However, a 10-year prostate cancer-specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group suggested that surveillance may be a suitable treatment for many patients with low-risk disease compared with the 19.2% 10-year risk of death from competing causes observed in the surveillance group and 10.2% in the curative-intent group of the total 6,849 person cohort.
Digital Rectal Exam
Although DRE has been used for many years, careful evaluation of this modality has yet to take place. 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.[7,8]
In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up. Thirty-eight of 43 patients with a palpable abnormality in the prostate agreed to undergo biopsy. The positive predictive value (PPV) of a palpable nodule, i.e., prostate cancer on biopsy, was 29% (11 of 38). Further evaluation revealed that 45% of the cases were stage B, 36% were stage C, and 18% were stage D. More results from the same investigators revealed a 25% PPV, with 68% of the detected tumors clinically localized but only approximately 30% pathologically localized after radical prostatectomy. Some investigators reported a high proportion of clinically localized disease when prostate cancer is detected by routine rectal examination, while others reported that even with annual rectal examination, only 20% of cases are localized at diagnosis. It has been reported that 25% of men presenting with metastatic disease had a normal prostate examination. Another case-control study examining screening with both DRE and PSA found a reduction in prostate cancer mortality that was not statistically significant (OR, 0.7; 95% CI, 0.46–1.1). Most men in this study were screened with DRE rather than PSA. All four of these case-control studies are consistent with a reduction of 20% to 30% in prostate cancer mortality. Potential biases inherent in this study design, however, limit the ability to draw conclusions on the basis of this evidence alone.
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%. A previous report from this same institution found DRE to have poor performance characteristics. Among 10,523 men randomly assigned to screening, it was reported that the overall prostate cancer detection rate using PSA, DRE, and TRUS was 4.5% compared with only 2.5% if DRE alone had been used. Among men with a PSA lower than 3.0 ng/mL, the PPV of DRE was only 4% to 11%. Despite the poor performance of DRE, a retrospective case-control study of men in Olmsted County, Minnesota, who died of prostate cancer found that case patients were less likely to have undergone DRE during the 10 years before diagnosis of prostate cancer (OR, 0.51; 95% CI, 0.31–0.84). These data suggested that screening DREs may prevent 50% to 70% of deaths from prostate cancer. Contrary to these findings, results from a case-control study of 150 men who ultimately died of prostate cancer were compared with 299 controls without disease. In this different population, a similar number of cases and controls had undergone DRE during the 10-year interval before prostate cancer diagnosis. One case-control study reported no statistically significant association between routine screening with DRE and occurrence of metastatic prostate cancer. The Prostate Cancer Prevention Trial (PCPT) requested all men undergo prostate biopsy at study end to address ascertainment bias; the sensitivity of DRE for prostate cancer was 16.7%. The sensitivity increased to 21.3% in men receiving finasteride.
Rectal 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.
Transrectal Ultrasound and Other Imaging Tests
Imaging procedures have been suggested as possible screening modalities for prostate cancer. Prostatic imaging is possible by ultrasound, computed tomography, and magnetic resonance imaging. Each modality has relative merits and disadvantages for distinguishing different features of prostate cancer. Ultrasound has received the most attention, having been examined by several investigators in observational settings. Sensitivity ranged from 71% to 92% for prostatic carcinoma and 60% to 85% for subclinical disease. Specificity values ranged from 49% to 79%, and PPV in the 30% range have been reported. The sensitivity and PPV for ultrasound as a single test may be better than for rectal examination. The rate of cancer is extremely low among ultrasound-positive patients in whom rectal and PSA examinations are normal. TRUS is generally relegated to a role in the diagnostic work-up of an abnormal screening test rather than in the screening algorithm. The cost and poor performance of other imaging modalities have led to their elimination from all early detection algorithms.
Contemporary prostate biopsy relies on spring-loaded biopsy devices that are either digitally guided or guided via ultrasound. TRUS guidance is the most frequently used method of directing prostate needle biopsy because there is some suggestion that the yield of biopsy is improved with such guidance. With the virtually simultaneous clinical acceptance of TRUS, spring-loaded biopsy devices, and the proliferation of PSA screening in the late 1980s, the number of prostate cores obtained from patients with either an abnormal DRE or PSA was most commonly six, using a sextant method of sampling the prostate. There is evidence that the predictable increase in cancer detection rates that would be expected by increasing the number of biopsy cores beyond six does occur; e.g., biopsies with 12 or 15 cores would increase the proportion of biopsied men having cancer detected by 30% to 35%.[25,26] The extent to which such increased detection will reduce morbidity and mortality from the disease or increase the fraction of men treated unnecessarily is unknown.
The PSA test has been examined in several observational settings for initial diagnosis of disease, as a tool to monitor for recurrence after initial therapy, and for prognosis of outcomes after therapy. There is no PSA value below which a man can be assured that he has no risk of prostate cancer. Parameter estimates for this test include sensitivity in the range of 70%.
In a review of the PCPT, 2,950 men who never had a PSA level higher than 4.0 ng/mL or an abnormal DRE had a final PSA determination and underwent a prostate biopsy after being in the study for 7 years. There was a 15.2% (n = 449) biopsy-proven prevalence of prostate cancer in men with PSA levels no higher than 4.0 ng/mL. High-grade prostate cancer (defined as Gleason score ≥7) was seen in 15.8% (n = 71) of these men. Size of the tumor was not reported.
In the placebo arm of the PCPT, there was no cutpoint of PSA with simultaneous high sensitivity and high specificity for detection of prostate cancer in healthy men, but rather a continuum of prostate cancer risk at all values of PSA.
The potential value of the test appears to be in its simplicity, objectivity, reproducibility, relative lack of invasiveness, and relatively low cost. PSA has increased the detection rate of early-stage cancers, some of which may be curable by local-modality therapies, but others of which do not require treatment.[30-33] Circumstantial evidence favoring screening for prostate cancer is analogous to that for lung cancer screening in the 1950s and 1960s; screening results in a shift to a higher proportion of cases with earlier-stage cancers at diagnosis. This shift may result in mortality reduction. For lung cancer, no mortality benefit resulted. However, 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).
A nested case-control prospective study with 10 years of follow-up reported that a single elevated PSA higher than 4.0 ng/mL predicted subsequent cancer with a sensitivity of 71% for the first 5 years and a specificity of 91% for the first 10 years of follow-up. The cancers diagnosed were characterized by stage and grade to be clinically important. Forty-two percent were extracapsular at diagnosis. Experience with repeat PSA screening suggests that tumors detected on follow-up examinations are of lower clinical stage and grade. Although a cutoff value of 4.0 ng/mL is frequently used to prompt prostate biopsy, screening studies have demonstrated that lowering the PSA cutoff will substantially increase the number of cancers detected, particularly in African Americans. In one study of the impact of race on PSA and tumor volume, these two variables were higher among African American men after adjustment for age, stage, pathologic stage, Gleason score, and volume of benign disease. Furthermore, lower cutoff PSA values are associated with a high proportion of negative biopsies (false-positives). An initial PSA lower than 2.5 ng/mL is associated with a very low risk of cancer detection within a 4-year follow-up.[36,40]
Probably the largest PSA/DRE early diagnosis experience comes from the Prostate Cancer Awareness Week program conducted at numerous sites around the United States. A report from that program indicates that of 116,073 participating men, if a 4.0 ng/mL PSA cutoff value was used, 22,014 men had an abnormal PSA, DRE, or both.
Various methods to improve the performance of PSA 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). This is likely because of a substantial biological or other variability in PSA levels in individual men. Several variables can affect PSA levels in men. Besides normal biological fluctuations that appear to occur,[41,42] pharmaceuticals such as finasteride (which reduces PSA by approximately 50%) and over-the-counter agents such as PC-SPES (an herbal agent that appears to have estrogenic effects) can affect PSA levels.[43,44] Some authors have suggested that ejaculation and DRE can also affect PSA levels, but subsequent examination of these variables have found that they do not have a clinically important effect on PSA. In any case, given this high variability, an elevated PSA should be confirmed by repeat testing before more invasive diagnostic tests are performed.
The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) 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 as the control (38,350 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. Results from the first four rounds of screening are shown in Table 1.
|DRE = digital rectal exam; PSA = prostate-specific antigen; T = tumor.|
|aAdapted from Grubb et al.|
|Number Tested (PSA or DRE)||34,262||32,696||31,697||30,544|
|PSA positive (>4 ng/mL) (%)||7.9||7.7||8.2||8.8|
|DRE positive (%)||7.2||6.8||7.3||7.6|
|Either test positive (%)||14.0||13.5||14.4||15.1|
|Biopsies and Cancers|
|PSA >4 ng/mL||2,718||2,502||2,593||2,676|
|DRE abnormal and PSA ≤4 ng/mL||2,083||1,923||1,973||1,943|
|PSA >4 ng/mL or DRE abnormal||4,801||4,425||4,566||4,619|
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% 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 (rate ratio, 1.13; 95% CI, 0.75–1.70). The data at 10 years were 67% complete and consistent with these overall findings (incidence rate ratio, 1.17; 95% CI, 1.11–1.22 and mortality rate ratio, 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.
At 7 years, the total numbers of deaths (excluding those from prostate, lung, or colorectal cancers) were 2,544 in the screening group and 2,596 in the control group (rate ratio, 0.98; 95% CI, 0.92–1.03); at 10 years, the numbers of such deaths were 3,953 and 4,058, respectively (rate ratio, 0.97; 95% CI, 0.93–1.01). The distribution of the causes of death was similar in the two groups.
The following are several possible explanations for the lack of a reduction in mortality so far in this trial:
- 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 level of screening in the control group could have been substantial enough to dilute any modest effect of annual screening in the screening 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.
- Potentially, the most important explanation is that improvement in therapy for prostate cancer during the course of the trial probably resulted in fewer prostate-cancer deaths in the two study groups, which blunted any potential benefits of screening.
- The follow-up may not be long enough for benefit from the earlier detection of an increased number of prostate cancers in the screening group to emerge.
- 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.
Prostate cancer mortality data from the PLCO cancer screening trial after 13 years of follow-up show no reduction in mortality due to prostate cancer screening with PSA and DRE. Organized screening in the intervention arm of the trial did not produce a mortality reduction compared with opportunistic screening in the control arm. There were no apparent interactions with age, baseline comorbidity, or pre-trial PSA testing as hypothesized in an intervening analysis by a subgroup analysis. These results are consistent with the prior 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 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 the 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 reports 45% of men in the PLCO trial had at least one PSA test in the 3 years prior to 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 arm was estimated to be half that in the intervention arm. Stage-specific treatment between the two arms was similar.
The European Randomized Study of Screening for Prostate Cancer (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. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 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 ended on December 31, 2006.
Recruitment and randomization procedures differed among countries and were developed in accordance with national regulations. In Finland, Sweden, and Italy, the trial subjects 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.
In the screening group, 82% of men accepted at least one offer of screening. With 14 years of data, and a median follow-up of 9 years, there were 5,990 prostate cancers diagnosed in the screening group and 4,307 in the control group, corresponding to a cumulative incidence of 8.2% and 4.8%, respectively. There were 214 prostate-cancer deaths in the screening group and 326 prostate cancer deaths in the control group in the core age group. The unadjusted rate ratio for death from prostate cancer in the screening group was 0.80 (95% CI, 0.67–0.95); after adjustment for sequential testing with alpha spending due to two previous interim analyses (based on Poisson regression analysis), the rate ratio was 0.80 (95% CI, 0.65–0.98). The rates of death in the two study groups began to diverge after 7 to 8 years and continued to diverge further over time.
The absolute difference between the screening and control groups was 0.71 prostate-cancer deaths per 1,000 men. Thus, to prevent one prostate-cancer death, the number of men who would need to be screened would be 1,410. The additional prostate cancers diagnosed by screening resulted in an increase in cumulative incidence of 34 per 1,000 men, so that 48 additional subjects would need to be treated to prevent one death from prostate cancer. Thus, PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis.
Important information that was not reported includes the contamination rate in the control group, and the treatment administered to the prostate cancer cases by stage and by randomly assigned group. 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 will be needed to determine the final results of this trial.
While the ERSPC demonstrated a 29% relative reduction in mortality from prostate cancer among men who were screened at 4-year intervals, there were associated harms from overdiagnosis and long-term treatment effects. Microsimulation Screening Analysis (MISCAN) was used to estimate the quality-adjusted life-years (QALYs) associated with annual PSA screening, based on results from the ERSPC trial. Health states considered in the analysis of QALYs included biopsy, cancer diagnosis, radiation therapy, radical prostatectomy, active surveillance, postrecovery period, palliative therapy and terminal illness. Adverse effects considered included overdiagnosis and various degrees of incontinence and erectile dysfunction. The model predicted that annual screening of 1,000 men aged 55 to 69 years would lead to nine fewer deaths from prostate cancer (98 men screened to prevent one prostate cancer death). Overall, 73 life-years would be gained, but QALYs gained was only 56 life-years on average with a range of -21 to 97 life-years. Screening men aged 55 to 74 years increased life-years gained but resulted in the same number of QALYs on average (56 life-years).
The Finnish Randomized Screening Trial is the largest component of the multicenter ERSPC consortium. Eighty thousand one hundred forty-four men born between 1929 and 1944 were identified from the Finnish Population Registry. Men with a previous prostate cancer diagnosis were excluded. Thirty one thousand eight hundred sixty-six men were randomly assigned to the screening arm (SA) and the remaining 48,278 men were randomly assigned to the control arm (CA). Randomization occurred annually from 1996 to 1999 (at ages 55, 59, 63, or 67 years at entry, which led to a similar age distribution in both arms). Men randomly assigned to the CA were not contacted. Men randomly assigned to the SA were invited to an initial screen, and if living in the study area and not already diagnosed with prostate cancer, were invited to second and third screenings at 4 and 8 years after randomization. Men with a PSA of 4.0 ng/mL or higher were referred to a local urological clinic for diagnosis. Men with a PSA of 3.0 to 3.99 ng/mL were referred to further testing. Median follow-up in both arms was 10.8 years. The screening arm had a nonstatistically significant reduction in prostate cancer mortality, based on an analysis of those who were invited to be screened. The hazard ratio between trial arms was 0.85 (95% CI, 0.69–1.04; P = .10). No screening effect was seen in all-cause mortality. Treatment differed between the two arms within each risk category. In all risk categories, radical prostatectomy was more common in the SA (statistically significant at P < .05 for moderate- and high-risk cancers) and radiation and endocrine treatment were more common in the CA (statistically significant at P < .05 for radiation in the moderate-risk category and for both radiation and endocrine treatment in the high-risk category). It was unknown whether this affected mortality. Contamination in the CA was not measured.
Possible harms included overdiagnosis, which was estimated at 30% on the basis of excess cases in the SA if the cumulative risk of prostate cancer had been the same as the CA.
The Goteborg (Sweden) trial is a prospective randomized trial of 20,000 men born between 1930 and 1944. Data from participants born between 1930 and 1939 is used in the pooled ERSPC data. Recently, data with up to 14 years of follow-up were reported. Of the screened group, 12.7% was diagnosed with prostate cancer versus 8.2% of the control group. The absolute risk of prostate death was 0.9% in the control group and 0.5% in the screening group (95% CI, 0.17–0.64). This is a 44% RR reduction in prostate-cancer mortality (95% CI, 0.28–0.68; P = .0002). Of note, the number of deaths from all causes was equal in the intervention group and the control group. The authors estimated that 12 men needed to be diagnosed and treated to prevent one death.
The Norrkoping (Sweden) 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 invited (every sixth man allocated to invited group) or not-invited groups. 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 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.
Because the efficacy of screening depends on the effectiveness of management of screen-detected lesions, trials of treatment efficacy in early-stage disease are relevant to the issue of screening. The Prostate Intervention Versus Observation Trial (PIVOT) is the only published trial conducted in the PSA era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer were randomly assigned to one of the two management strategies. About 50% of the men had nonpalpable, screen-detected disease. After a median follow-up of 10 years (maximum up to about 15 years), there was no statistically significant difference in overall or prostate-specific mortality. (Refer to the Treatment Option Overview section in the PDQ summary on Prostate Cancer Treatment for a more detailed description of the study and results.)
Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer
As noted above, various approaches aimed at improving the performance of PSA in early cancer detection have been tested. None are clearly more accurate than total serum PSA levels, but these approaches are discussed below.
Prostate cancer gene 3 (PCA3)
PCA3 was approved by the U.S. Food and Drug Administration in early 2012, with the intended use to improve the selection of men with a prior negative biopsy for an elevated PSA for whom a repeat biopsy is being considered for a persistently elevated PSA. This test is performed in a urine sample collected after an "attentive" DRE (several strokes applied firmly to the prostate to 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 will ultimately have a negative biopsy.
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%, 15.6%, and 26.7%. The preponderance of evidence concerning the utility of complexed and percent-free PSA is not clear, however, total PSA remains the standard.
A number of authors have considered whether complexed PSA or percent-free PSA in conjunction with total PSA can improve the latter’s 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), sensitivity/specificity ranged from about 45%/95% to 95%/15%.
Percent-free PSA may be related to biologic activity of the tumor. One study compared the percent-free PSA with the pathologic 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. Similar findings were reported in another large series.
The third-generation (ultrasensitive) PSA test is an enzyme immunometric assay intended strictly (or solely) as an aid in the management of prostate cancer patients. The clinical usefulness of this assay as a diagnostic or screening test is unproven.[61,62]
Because larger prostates caused by increased amounts of transition-zone hyperplasia are known to be associated with higher serum PSA levels, reports have suggested indexing PSA to gland volume, using a measure known as PSA density. PSA density is defined as serum PSA divided by gland volume. Generally, ultrasound is used to measure gland volume. While early studies suggested that this measure may discriminate between patients with cancer and those with benign disease, subsequent evaluations have failed to confirm any clinically useful association.[64,65]
PSA density of the transition zone
PSA density of the transition zone (serum PSA divided by the volume of the transition zone) has been suggested to better adjust for benign sources of PSA. One study prospectively evaluated 559 men with PSA levels between 4.0 ng/mL and 10.0 ng/mL. A total of 217 of these men were ultimately found to have prostate cancer; of all PSA variants analyzed, percent-free PSA and PSA density of the transition zone were found to have the best predictive value (area under the receiver operator curve values of 0.78 and 0.83). Another study also found that PSA density of the transition zone had superior performance characteristics. In this study of 308 volunteers undergoing first-time screening, it was reported that the combination of percent-free PSA (<20%) and PSA density of the transition zone resulted in elimination of 54.2% of biopsies that ultimately proved to be benign.
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. While age adjustment tends to improve sensitivity for younger men and specificity for older men, the trade-off in terms of more biopsies in younger men and potentially missed cancers in older men has prevented uniform acceptance of this approach.
A study using frozen serum from 18 patients concluded that an annual rise of PSA level of 0.8% ng/mL warranted a prostate biopsy. In a follow-up study that used serum collected serially from men without known prostate cancer (two groups with benign prostatic hyperplasia, one diagnosed by histology and the other clinically, both with PSA levels no higher than 10 ng/mL, and a third group with no more than one PSA exceeding 10 ng/mL), it was reported that averaging three PSA changes measured at 2-year intervals could be useful for cancer discrimination, while changes measured at 3-month or 6-month intervals were volatile and nonspecific, perhaps because of a biologic fluctuation of PSA that may be as high as 30%.[42,70] One study followed 1,249 men screened by PSA and concluded that patients with a 20% annual increase in their PSA level should undergo further evaluation.
A study specifically tested whether total PSA velocity (tPSAv) improves the accuracy of total PSA level (tPSA) to predict long-term risk of prostate cancer. In the 1974 to 1986 Swedish Malmo Preventive Medicine cardiovascular risk study, 5,722 men younger than 51 years gave two blood samples about 6 years apart. Four thousand nine hundred-seven of the archived plasma samples were analyzed for tPSA. Prostate cancer was subsequently diagnosed in 443 (9%) of the men via the Swedish National Cancer Registry through December 31, 2003. Cox proportional hazards regression was used to evaluate tPSA and tPSAv as predictors of prostate cancer. Predictive accuracy was assessed by the concordance index (similar to the area under the receiver operating characteristic).
The median time from the second blood draw to cancer diagnosis was 16 years. Median follow-up for men not diagnosed with prostate cancer was 21 years. PSA assays were done in plasma stored under conditions that preserved the integrity of PSA. TPSA and tPSAv were highly correlated. Both tPSA and tPSAv were associated with prostate cancer in univariate models (P < .001). Men subsequently diagnosed with prostate cancer have increased tPSA and increased tPSAv up to 20 years before diagnosis. Overall predictive accuracy of tPSA plus tPSAv was equivalent to tPSA alone (concordance index: 0.771 tPSA alone; 0.712 tPSAv alone; 0.771 tPSAv added to tPSA). TPSAv did not aid long-term prediction of cancer in early middle-aged men.
In the PCPT, 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/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. Several collaborating European jurisdictions are conducting prostate cancer screening trials, Rotterdam (the Netherlands) and Finland among them. In Rotterdam, data for 7,943 screened men between the ages of 55 and 74 years have been reported. Of the 534 men who had PSA levels between 3.0 ng/mL and 3.9 ng/mL, 446 (83.5%) had biopsies and 96 (18%) of these had prostate cancer. In all, 4.7% of the screened population had prostate cancer. In Finland, 15,685 men were screened and 14% of screened men had PSA levels of at least 3.0 ng/mL. All men with PSAs higher than 4.0 ng/mL were recommended to diagnostic follow-up by DRE, ultrasound, and biopsy; 92% complied, and 2.6% of the 15,685 men screened were diagnosed with prostate cancer. Of the 801 men with screening PSAs between 3.0 ng/mL and 3.9 ng/mL (all biopsied), 22 (3%) had cancer. Of the 1,116 men with screening PSAs between 4.0 ng/mL and 9.9 ng/mL, 247 (22%) had cancer; of the 226 men with screening PSAs of at least 10 ng/mL, 139 (62%) had cancer. Several factors could have contributed to these differences, including background prostate cancer prevalence, background screening levels, and details regarding diagnostic follow-up practices; the necessary comparative data are not available.
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 cc (range, 0.6–4.4). The extent of disease was significant in a number of cases, with positive margins in five cases and pathologic pT3 disease in six cases.
Frequency of screening
The optimal frequency and age range for PSA (and DRE) testing are unknown.[68,76,77] Cancer detection rates have been reported to be similar for intervals of 1 to 4 years. With serial annual screening in the PLCO trial, 8% of men with baseline PSA lower than 1 ng/mL had a prostate cancer diagnosis within 2 years. In the same trial, 2-year intervals in screening produced average delays of 5.4 to 6.5 months, while 4-year screening intervals produced average delays of 15.6 months (baseline PSA < 1 ng/mL) to 20.9 months (baseline PSA 3–4 ng/mL). While the authors caution that an optimal prostate screening frequency cannot be determined from these data, they conclude that among men who choose to be screened, these data may provide a context for determining a PSA screening schedule.
A report from the ERSPC trials demonstrated that while more frequent screenings lead to more diagnosed cancers, the detection rates for aggressive interval cancers was very similar with the different screening intervals in place in the two countries reporting (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) trials should facilitate a more reliable assessment of the benefits and costs of different screening intervals.
Types of Tumors Detected by Prostate Cancer Screening
Of serious concern with regard to prostate cancer screening is the high background histologic prevalence of the disease. It has been demonstrated that a considerable fraction (approximately one-third) of men in their fourth and fifth decades have histologically evident prostate cancer. Most of these tumors are well-differentiated and microscopic in size. Conversely, evidence suggests that tumors of potential clinical importance are larger and of higher grade. Since the inception of PSA screening, several events have occurred: (1) a contemporaneous but unrelated decrease in detections of transition-zone tumors caused by a fall in the number of transurethral resections of the prostate due to the advent of effective treatment for benign prostatic hyperplasia (including alpha blockers and finasteride); and (2) an increase in detection of peripheral-zone tumors due to the incorporation of TRUS-guided prostate biopsies. Because transition-zone tumors are predominantly low volume and low grade and because peripheral-zone tumors have a preponderance of moderate-grade and high-grade disease, the proportion of higher grade tumors detected by current screening practices has increased substantially. A Detroit study found that between 1989 and 1996, poorly differentiated tumors remained stable and well-differentiated tumors fell in frequency while moderately differentiated disease increased in frequency. The largest rise in incidence was in clinically localized disease. It is now known that systematic changes to the histological interpretation of biopsy specimens by anatomical pathologists has occurred during the PSA screening era (i.e., since about 1985) in the United States. This phenomenon, sometimes called “grade inflation,” is the apparent increase in the distribution of high-grade tumors in the population over time but in the absence of a true biological or clinical change. It is possibly the result of an increasing tendency for pathologists to read tumor grade as more aggressive.
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 for prostate cancer. PSA does not appear to be elevated with PIN.[86,87]
Physician Behaviors Related to Screening
A variety of variables affect the likelihood of a recommendation for prostate cancer screening from a physician. In Washington State, 1,369 primary care physicians were surveyed to determine patterns of PSA screening recommendations. Of the 714 respondents, 68% routinely recommended PSA screening. The survey results suggest that gender (male), age (medical school graduation before 1974), and mode of reimbursement (fee for service) all increase the likelihood of PSA screening recommendations among this population.
Randomized Prospective Clinical Trials of Screening for Prostate Cancer
While two large randomized clinical trials are under way to assess whether early detection of prostate cancer can reduce mortality from the disease,[89,90] a Canadian trial has been reported to have been performed in a randomized prospective manner. In this 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. (It appears that these men were unaware that they had been enrolled in a randomized clinical trial.) A notable difference from other screening studies was that a PSA of 3.0 ng/mL was used to determine whether further evaluation was warranted. In this study (in which the patient numbers have been variously reported by the authors) of the 31,133 men who were randomly assigned to screening, 7,348 actually underwent screening while 23,785 did not. Of the 15,353 who were randomly assigned to observation, 1,122 actually underwent screening while 14,231 did not. Two hundred-seventeen deaths were noted among the 38,016 men who did not undergo screening, compared with only 11 deaths among the 8,470 men who underwent screening. Using an intention-to-treat analysis based on the study arm to which an individual was originally assigned, however, no difference in mortality was seen (there were 75 deaths among the 15,353 men who were randomly assigned to observation compared with 153 deaths among the 31,133 men randomly assigned to screening [RR, 1.085]). Because of noncompliance, this study does not answer the question of whether early detection with PSA will reduce prostate cancer mortality.
Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality
While DRE has been a staple of medical practice for many decades, 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 of 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 (NCI'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.
Since 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. Similar observations have been made elsewhere in the world,[95,96] leading some to hypothesize that the mortality decline is related to PSA testing. In Quebec, Canada, however, examinations of the association between the size of the rise in incidence rates (1989–1993) and the size of the decrease in mortality rates (1995–1999), by birth cohort and residential grouping, showed no correlation between these two variables. This study suggests that, at least during this time frame, the decline in mortality is not related to widespread PSA testing.
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 have been diagnosed with prostate cancer are mislabeled as dying 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. Since the evidence in this respect is inconsistent, it remains unclear whether the causes of these mortality trends are chance, misclassification, early detection, improved treatments, or a combination of effects.
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 pathologic 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. Grades range from 1 to 5, with 1 being the most differentiated and 5 the least differentiated. Grade 3 tumors seldom have associated metastases, but metastases are common with grade 4 or grade 5 tumors. The two grades are added together to produce a Gleason score. A score of 2 to 4 is rarely given, 5 to 6 is low grade, 7 is intermediate grade, and 8 to 10 is high grade. The overall rate of concordance between original interpretations and review of the needle biopsy specimens has been reported to be 60%, with accuracy improving with increased tumor grade and percentage of tumor involvement in the biopsy specimen.
As of 2005, approximately 90% of prostate cancers detected are clinically localized and have more favorable tumor characteristics or grades than the pre-PSA screening era. A retrospective population-cohort study using the Connecticut Tumor registry reviewed the mortality probability from prostate cancer given the patient’s age at diagnosis and tumor grade. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. This study was initiated before the PSA screening era. Transurethral resection or open surgery for benign prostatic hyperplasia identified 71% of the tumors incidentally. The prostate cancer mortality rate was 33 per 1,000 person-years during the first 15 years of follow-up (95% CI, 28–38) and 18 per 1,000 person-years after 15 years of follow-up (95% CI, 10–29). Men with low-grade prostate cancers had a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2 to 4; six deaths per 1,000 person-years; 95% CI, 2–11). Men with high-grade prostate cancers had an increased probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8 to 10, 121 deaths per 1,000 person-years; 95% CI, 90–156). Men with tumors that had a Gleason score of 5 or 6 had an intermediate risk of prostate cancer death. The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis.
A computer simulation model has been developed to analyze the trends in prostate cancer detection (PSA screening beginning in approximately 1988) to compare these trends with the reported fall in prostate cancer deaths observed between 1992 and 1994. The level of screening efficacy was hypothesized to be similar to those postulated in the PLCO. The changes in prostate cancer mortality could not be explained entirely by PSA screening alone.
Decision analyses using the Markov model yield variable treatment outcomes because of the uncertainty regarding metastatic rates expected for prostate cancer and uncertainty about treatment efficacy.[104-106] A review of 59,876 men with prostate cancer diagnosed between 1983 and 1992 and registered by the SEER registries, however, shows that treatment of men with poorly differentiated and moderately differentiated disease is associated with an improved survival rate, compared with observation. It is not known to what degree this can be attributed to treatment effect as opposed to other factors such as a preponderance of relatively healthy patients in the treated group. The information from Swedish studies of expectant therapy lead to different conclusions depending on methodology and populations used in analysis.
Simulation modeling from the NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) program suggests that changes in prostate cancer treatment explain a portion of the drop in prostate cancer mortality but that most of the decline is likely the result of other factors such as screening or improvements in disease management after primary therapy.
A simulation model based on available evidence suggests that if there is a benefit to screening, this benefit decreases with age. No trial of prostate cancer screening in which the intervention arms were analyzed as randomized (analogous to an intention-to-treat analysis in a treatment trial) has been reported. There is insufficient evidence on which to decide the efficacy of TRUS and serum tumor markers (including PSA) for routine screening in asymptomatic men.[104,111]
Providing Information to the Public, to Patients, and to Their Families
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 what information may help to inform a man undertaking a decision regarding PSA screening. At a minimum, men should be informed about the possibility that false-positive or false-negative test results can occur, that it is not known whether regular screening will reduce the number of deaths from prostate cancer, and that among experts, the recommendation to screen is controversial. The PLCO-1, which is now closed to accrual, is following participants to test the effect of early detection by DRE and PSA on reducing mortality. A trial of screening is also being performed in Europe.[89,113]
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