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A "Slightly High" PSA:
Published on Cancer Network (http://www.cancernetwork.com)
A "Slightly High" PSA:
April 01, 2005 | Prostate Cancer [1]
By David E. Rapp, MD [2] and Glenn S. Gerber, MD [3]
ABSTRACT: Although the widespread use of prostate-specific antigen (PSA) testing has
led to an increase in the number of cancers detected, controversies about the benefits of
screening persist. No conclusive evidence has yet emerged that PSA screening reduces
the mortality associated with prostate cancer. Thus, mass screening is not universally
endorsed. The American Urologic Association and the American Cancer Society
recommend that digital rectal examination and PSA testing be offered annually to men
50 years and older with an estimated life expec- tancy of 10 years or more. High-risk
patients (those with a positive family history or those of African American descent) are
advised to begin screening at age 45. The decision to screen is based on the patient's
preference following a thorough discussion of the benefits and limitations of PSA testing.
Refer to a urologist any patient with a PSA greater than 4.0 ng/mL. Also, be alert for high
PSA velocity changes in patients undergoing annual screening, and refer those with a
PSA velocity of more than 0.75 ng/mL/y.
A 57-year-old white man with no urologic symptoms and no family history of prostate cancer
requests a prostate- specific antigen (PSA) test. What will you tell him?
Prostate cancer detection and treatment have been profoundly affected by the advent of PSA
testing. Nonetheless, the specificity and sensitivity of the assay are imperfect, which has resulted in
disagreement about the test's accuracy in the diagnosis of cancer and the overall treatment benefit
of mass PSA screening. Data are not yet available from randomized trials to determine whether early
detection is beneficial or harmful or has no effect. Consequently, the optimal strategy for early
detection with PSA testing remains unclear.
Current clinical guidelines and the evolving refinement of PSA assays have addressed some of these
concerns. However, further standardization of screening and treatment guidelines is needed.
In this article, we review the principal risks and benefits of screening and highlight important areas
of controversy.THE IMPACT OF PSA TESTING
PSA--a serine protease produced by the epithelial cells of the prostate gland--is secreted into the
prostatic ducts and aids in the liquefaction of semen.1 Early investigation revealed that PSA was
specific to the prostate gland, which suggested that this antigen might be helpful in the diagnosis
and/or treatment of prostate cancer.2 In 1986, the FDA approved PSA testing for use in the
monitoring of prostate cancer recurrence following prostatectomy.3 PSA testing was approved by the
FDA for prostate cancer screening in 1994 and has had a substantial impact on the detection and
treatment of prostate cancer.3
The principal result of PSA testing has been the increasing number of cancers detected annually.4
Not surprisingly, this trend has paralleled an increase in prostate cancer cases diagnosed as a result
of elevated PSA levels. Data reported approximately 10 years after the introduction of PSA testing
revealed that prostate cancer detection as a result of PSA elevation had become as common as
detection through an abnormal digital rectal examination (DRE) and was far more common than
incidental discovery following transurethral resection of the prostate in the treatment of benign
prostatic hyperplasia (BPH).5 As a result of this trend, cancer confined to the prostate is being
diagnosed in a larger number of patients, with a corresponding reduction in the incidence of lymph
node metastases detected during radical prostatectomy.5,6
Despite these trends, several concerns remain. Earlier diagnosis of organ-confined disease has been
accompanied by advances in the surgical techniques used in radical prostatectomy, which should,
theoretically, result in improved cancer-specific survival. However, Soh and colleagues5 found no
change in pathologic stage or prognosis for patients treated during a 12-year period before and after
the introduction of PSA screening. In addition, randomized controlled trials have not conclusively
demonstrated that PSA screening reduces the mortality associated with prostate cancer.7PSA
CONTROVERSIES
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Usefulness of PSA screening. Although the detection of increasing numbers of prostate cancers
through PSA screening might seem an important accomplishment, autopsy data show that 80% of
men in their 70s have prostate cancer.8 Significant, potentially life-threatening disease develops in
only a small percentage of men.
Data that were obtained around the time PSA screening was introduced showed a correlation
between PSA level and tumor volume. Large tumor volume, in turn, suggested more aggressive
disease.9 However, recent data have demonstrated that the relationship between PSA level and
tumor volume has disappeared, which has led some authors to conclude that the PSA screening era
is "over."9
Accordingly, the concept of clinically insignificant prostate cancer has been developed, and research
has increasingly focused on the use of pathologic variables (such as Gleason grade and tumor
volume) to better define cancers that may be more indolent.10 Despite these steps, it is still not
possible to identify aggressive tumors selectively. For this reason, controversy remains centered
around the utility of mass screening programs and the potential for overdiagnosis.
Benefits of intervention. Controversy surrounding PSA screening is also related to the natural
course of prostate cancer and the variable benefit of intervention in patients in whom the disease is
diagnosed. A seminal report by Pound and associates11 found a median actuarial time of 8 years
from the recurrence of PSA elevation after radical prostatectomy to the development of metastatic
disease. An additional 5-year actuarial time from metastatic disease to death was reported in these
patients.
Based on these data, it is evident that aggressive intervention is warranted only in those patients
with an appropriate life expectancy, because a significant number of patients--even those with
untreated prostate cancer--will die of other causes. Further, because of the slow rate of disease
progression in most patients, a lengthy window of opportunity may exist for treatment. Therefore,
immediate intervention is not always mandatory, especially for patients in whom life expectancy
may be limited.Based on these considerations, some authors advocate watchful waiting as an
acceptable treatment approach in patients with a limited life expectancy or in those with less
aggressive tumors.12,13However, selection of patients for whom expectant management is
appropriate remains difficult.
Sensitivity of PSA. Much attention has been paid to the lack of specificity of PSA for prostate
cancer; however, controversy also exists about the assay's sensitivity. Although the commonly used
PSA threshold of 4.0 ng/mL results in reasonable sensitivity, some experts believe that a lower PSA
threshold is needed to increase cancer detection.14 However, lowering the PSA threshold for prostate
biopsy would probably heighten existing concerns about overdiagnosis of indolent disease.10 These
concerns have led researchers to attempt to identify cancers with a lower potential for progression
and death.15SCREENING GUIDELINES
Although PSA testing has undoubtedly enhanced the ability to detect prostate cancer, the lack of
specificity has resulted in considerable controversy about such questions as standardization of
reference ranges and the appropriate indications for prostate biopsy. The lack of consensus is most
evident in recent clinical guidelines for PSA screening, which vary considerably between
organizations, and in the differing approaches to routine screening observed in primary care
practices.16
The latest American Urologic Association and American Cancer Society guidelines recommend that
prostate cancer screening be offered annually to men 50 years and older with an estimated life
expectancy of 10 years or more.17,18 High-risk patients (those with a positive family history or those
of African American descent) are advised to begin screening at age 45 years. According to these
groups, prostate cancer screening should include both PSA measurement and DRE. Other
organizations, such as the US Preventive Services Task Force, believe that there is insufficient
evidence to support prostate cancer screening.3 The CDC does not recommend routine screening
because of the lack of consensus about the benefits of PSA screening with regard to mortality.19
Despite this controversy, most clinical guidelines--including those of the American College of
PhysiciansAmerican Society of Internal Medicine and the American Academy of Family
Physicians--suggest that screening decisions be individualized based on patient preference, following
an informed discussion that addresses the benefits and limitations of screening (Box).
A discussion of these issues is equally important in patients with a life expectancy of less than 10
years. Although we recommend against routine PSA screening in this group,we find that patients are
often uncomfortable with the decision to forgo PSA screening, largely because of widespread
publicity about this test. In these cases, a reasonable alternative to annual PSA screening is a
one-time PSA measurement, with follow-up based on the initial result.
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The same concerns are also important in deciding when to discontinue annual PSA testing in patients
of advancing age who have undergone screening for many years.We suggest to our patients who
choose to forgo PSA screening that we would like to continue to perform an annual DRE, which may
detect, and allow for treatment of, high-volume or more aggressive prostate cancers.PSA
REFERENCE RANGE
Based on early investigations that demonstrated an increased risk of prostate cancer in men with a
PSA level greater than 4.0 ng/mL, this level is typically used as the threshold to recommend prostate
biopsy.20 Nevertheless, the sensitivity of this level is limited. Table 1 illustrates the associated
probability of cancer detection by subsequent biopsy stratified by various PSA ranges. More than
30% of men with organ-confined prostate cancer may have a PSA level of less than 4.0 ng/mL.21,22
Based on recent investigation, some authors recommend that a threshold of 2.5 ng/mL be used to
recommend prostate biopsy.14 Related research suggests that a higher percentage of patients may
receive a diagnosis of organ-confined cancer with use of this threshold and that this adjustment will
not result in overdetection of clinically insignificant prostate cancer.3 However, other authors remain
concerned that lowering PSA reference ranges will result in the diagnosis of more cases of clinically
indolent disease.10
Additional questions about the appropriate PSA reference range are related to PSA variations that
may result from a patient's age or race (Table 2). Thus, some investigators have suggested that
age-specific and race-specific reference ranges may be helpful.23,24 However, evidence indicates that
a significant number of cancers will remain undetected even with the use of modified reference
ranges.25
Because no data have conclusively demonstrated that modified reference ranges improve outcomes,
we continue to recommend prostate biopsy in patients with a PSA level greater than 4.0 ng/mL. In
patients at increased risk and in those younger than 55 years with PSA values of 2.5 to 4.0 ng/mL,
we may use supplemental PSA assays (detailed below) to further help stratify risk, but we would
more commonly recommend biopsy.OPTIMIZING PSA ACCURACY
Serum PSA elevation is seen in a number of benign processes, including BPH, urinary retention,
recent ejaculation, urethral catheterization, and prostatitis.3 Although some experts recommend that
PSA measurement be avoided within 1 week of DRE, evidence suggests that DRE has minimal or no
effect on serum PSA concentration in the range below 20 ng/mL.26 We most commonly measure PSA
before the DRE, although this is not mandatory. Other evidence has shown that elevated PSA levels
are associated with cycling; this has led some authors to recommend against PSA testing within 1
week of this activity.27A newer study did not find a connection between cycling and PSA levels.28
Nonetheless,we advise patients to avoid cycling and sexual activity during the week before PSA
measurement.
We routinely obtain a urinalysis as part of the annual physical examination, which serves to exclude
any infectious cause for PSA elevation. If a patient presents with symptoms that suggest a urinary
tract infection, a complete urinalysis and microscopic examination are warranted. If you suspect that
the PSA level is spuriously elevated, it is reasonable to repeat the measurement after an appropriate
interval (eg, 4 to 6 weeks).OTHER PSA ASSAYS
A number of assays are commonly used by urologists to help distinguish between benign and
malignant causes of PSA elevation.
PSA velocity. This is defined as the rate of rise in PSA level over time. Interest in PSA velocity was
based on the premise that the rapidity of cell division associated with prostate cancer might be
greater than that associated with BPH. An increase in the serum PSA of 0.75 ng/mL/y or more
suggests prostate cancer.29 Using this threshold, PSA velocity has been associated with a specificity
of 95% in men with PSA values below 10 ng/mL.20
PSA density (PSAD). This is defined as the serum PSA divided by prostate volume. PSAD
measurement was introduced in an attempt to control for PSA elevation resulting from BPH. A PSAD
greater than 0.15 ng/mL/cc is reported to indicate cancer, although some experts believe that this
cutoff results in many missed cancers.20,30 Further, measurement of PSAD requires transrectal
ultrasonography, which is associated with additional cost and discomfort.
Total, free, and complexed PSA. Serum PSA is present in 2 general forms--free PSA (fPSA) and
complexed PSA (cPSA). Most of the PSA that enters the systemic circulation becomes complexed to
protease inhibitors, the most common of which is alpha-1-antichymotrypsin. The relative percentage
of fPSA to total PSA (tPSA) is known as %fPSA. Investigation has shown that men with prostate
cancer are more likely to have a lower %fPSA than those who do not have prostate cancer.20
Currently, there is no consensus regarding the %fPSA threshold at which biopsy is recommended;
%fPSA is used instead to further stratify the risk of patients with an elevated PSA value. For example,
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a %fPSA greater than 20% is associated with an 8% risk that cancer will be detected on subsequent
biopsy, whereas a %fPSA of less than 10% is associated with cancer in 46% of patients.31
We find that a %fPSA assay is most useful when it is unclear whether a biopsy is necessary. In such
cases, we recommend biopsy for patients with a %fPSA of less than 10%. If the %fPSA is greater than
20%, we usually wait and repeat the test in 6 to 12 months.
Usefulness of assays. A true determination of the utility of these assays remains difficult. We
believe that these tests may be used to complement routine tPSA measurement. They are most
useful in the PSA "gray zone"--that is, the range between 4 and 10 ng/mL. They are also helpful in
guiding the decision to perform repeated prostate biopsy in patients in whom previous biopsy
yielded no evidence of cancer but who consistently have elevated and/or increasing PSA levels.
Accordingly, in our practice, patients with a tPSA of more than 4 ng/mL and a life expectancy of at
least 10 years are routinely offered prostate biopsy. In addition, the finding of a palpably abnormal
prostate that suggests malignancy generally warrants biopsy, irrespective of PSA level. Patients who
have no evidence of malignancy on prostate biopsy are then monitored closely, and a repeated tPSA
is performed annually or semiannually. In these patients, we often follow tPSA with a combination of
PSA velocity, %fPSA, and/or cPSA assays. Although some literature suggests that the %fPSA may
serve as a more specific marker of cancer than does PSAD or PSA velocity, no clear evidence
suggests the superiority of any single assay.32
Controversy exists about the benefit of supplemental assays in patients with PSA values less than
4.0 ng/mL. For example, whereas some investigators believe that PSA velocity is useful in patients
with a PSA level in this range, others think that assay specificity is more limiting.3,20,33 Despite this
controversy, we believe that a high PSA velocity, even with a tPSA of less than 4.0 ng/mL, is cause
for concern, and that closer follow-up and/or additional PSA assays may be useful in this setting.
The power of any PSA assay to detect prostate cancer is limited. For this reason, we suggest that any
patient with a PSA greater than 4.0 ng/mL be referred to a urologist for further counseling and/or
intervention. Further, we recommend that you also be alert for high PSA velocity changes in patients
undergoing annual screening and refer those with a PSA velocity of more than 0.75 ng/mL/y.
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