Evidence of Benefit
Digital Rectal Exam
Transrectal Ultrasound and Other Imaging Tests
Prostate-Specific Antigen
Methods to Improve the Performance of Serum PSA Measurement for the Early Detection of Prostate Cancer
Complexed PSA and percent-free PSA
Third-generation PSA
PSA density
PSA density of the transition zone
Age-adjusted PSA
PSA velocity
Alteration of PSA cutoff level
Frequency of screening
Types of Tumors Detected by Prostate Cancer Screening
Physician Behaviors Related to Screening
Randomized Prospective Clinical Trials of Screening for Prostate Cancer
Population Observations on Early Detection, Incidence, and Prostate Cancer Mortality
Simulation Models
Providing Information to the Public, to Patients, and to Their Families
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.[1] 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.[2]
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.[3]
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.[4] 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 20 men with palpable, clinically localized prostate cancer would require radical prostatectomy rather than watchful waiting to extend the life of one man. 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.[5]
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.[6,7]
In 1984, one study reported on 811 unselected patients aged 50 to 80 years who underwent rectal examination and follow-up.[8] 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% positive predictive value, with 68% of the
detected tumors clinically localized but only approximately 30% pathologically
localized after radical prostatectomy.[9] Some investigators reported a high proportion of clinically localized disease when prostate cancer
is detected by routine rectal examination,[10] while others reported that even
with annual rectal examination, only 20% of cases are localized at
diagnosis.[11] It has been reported that 25% of men
presenting with metastatic disease had a normal prostate examination.[12]
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.[13] 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%.[14]
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%.[15] 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.[16] 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.[17] One
case-control study reported no statistically significant association between
routine screening with DRE and occurrence of metastatic
prostate cancer.[18]
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 to 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.[19] Sensitivity ranged from 71% to 92% for prostatic carcinoma and
60% to 85% for subclinical disease. Specificity values ranged from 49% to 79%,
and positive predictive values in the 30% range have been reported. The
sensitivity and positive predictive value 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.[20] 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.[21] 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.[22] 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%.[23,24] 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.
Prostate-Specific Antigen
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%.[25]
In a review of the Prostate Cancer Prevention Trial, 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.[26] 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 Prostate Cancer Prevention Trial, 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.[27]
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, many of which may be curable by local-modality
therapies.[28-31] 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.[32] 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.[33]
Experience with repeat PSA screening suggests that tumors detected on follow-up
examinations are of lower clinical stage and grade.[34] 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.[35] 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.[36] Furthermore,
lower cutoff PSA values are associated with a high proportion of
negative biopsies (false-positives).[37] 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.[34,38]
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).[39] 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,[39,40] 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.[41,42] 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.[43] 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 cancer on disease-specific mortality. Enrollment began in November 1993 and concluded in June 2001. Participants were randomly assigned to the screening or control arm. A total of 76,705 men were enrolled, 38,250 of whom were assigned to the screening arm. Of these, 34,244 men underwent an initial PSA and/or DRE screening examination. Compliance rates for PSA and DRE were roughly equivalent at 89%. More than 99% of men who underwent screening with either PSA or DRE received both screening tests.[44]
Summary of PLCO Trial Resultsa
Screening Test Administered
|
PSA
|
DRE
|
PSA or DRE
|
Number of Men Receiving Test
|
34,233 |
34,115 |
34,224 |
Positive Test (%): DRE Suspicious for Cancer; PSA >4 ng/mL
|
2,717 (7.9) |
2,482 (7.3) |
4,801 (14.1) |
Biopsies (% of positives)
|
1,112 (40.9) |
639 (25.7) |
1,510 (31.5) |
Prostate Cancer (% of biopsies)
|
489 (44.0) |
219 (34.3) |
556 (36.8) |
Prostate Cancer (% of positives)
|
489 (18.0) |
219 (8.8) |
556 (11.6) |
DRE = digital rectal exam; PSA = prostate-specific antigen.
|
aProstate cancer diagnosis rates increased as PSA concentrations increased among both DRE-positive and DRE-negative men.[44]
|
The trial has not yet reached mortality endpoints.
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.
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%.[45] 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%.[46]
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.[47] Similar
findings were reported in another large series.[48]
Third-generation PSA
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.[49,50]
PSA density
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,[51] subsequent evaluations have failed to confirm
any clinically useful association.[52,53]
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).[54]
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.[55]
Age-adjusted PSA
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.[56] 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.
PSA velocity
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.[57] 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%.[40,58] 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.[59]
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).[60]
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.[60]
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.[35] 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.[61] 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.[62]
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.[37]
Frequency of screening
The optimal frequency and age range for PSA (and DRE) testing are
unknown.[56,63,64] Cancer detection rates have been reported to be similar for intervals of 1 to 4 years.[65] 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.[66] 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).[66] 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 European Randomized Study of Screening for Prostate Cancer (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.[67]
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.[68] 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.[69] 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.[70] 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.[71] 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.[72]
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.[73,74]
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.[75]
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,[76,77] 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.[78]
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.[79]
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 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.[80]
Since the outset of PSA screening beginning around 1988, incidence rates
initially rose dramatically and then 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.[81] Similar observations
have been made elsewhere in the world,[82,83] 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.[83] 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.[84] 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.[85]
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.[86] 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 considered low grade, 5 to 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.[87]
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.[88] 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.[89] 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.[89]
Simulation Models
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.[90]
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.[91-93] 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.[94] 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.[95]
A simulation model based on available evidence suggests that if there is a
benefit to screening, this benefit decreases with age.[96] 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.[91,97]
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.[98] 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.[76,99]
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