Resolution 511 (I-99) Methods
Introduction Principles of Screening Criteria of Effective Screening Tests Variables That Confound Assessment of Screening Tests	Effectiveness of Treatment Randomized Trials Underway Treatment Screening
National Trends in the Epidemiology of Prostate Cancer	Potential Harm Associated With Screening & TreatmentCost-Effectiveness Informed Consent
Effectiveness of Tests for Early Detection Digital Rectal Examination (DRE) Prostate-Specific Antigen (PSA) Combined Use of DRE and PSA Efforts to Enhance PSA Specificity   PSA Density (PSAD)   PSA Velocity   Age- & Race-specific PSA   Reference Ranges   Molecular Forms of PSA	Summary & Conclusion Recommendations (Adopted AMA Policy) References Tables Table 1. Current Guidelines on Prostate Cancer Screening Table 2. Prostate Cancer Tumor Staging (TNM System)

    

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NOTE: This report of the American Medical Association Council on Scientific Affairs represents the medical/scientific literature on this subject as of June 2000.

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Methods

Published studies from the years 1988 to March 2000 were identified through MEDLINE and Lexis/Nexis Medical Library searches for English-language articles using the key words prostatic neoplasms, palpation, prostate-specific antigen, and mass screening, cross-indexed with the additional MeSH terms prevention and control, tumor markers, sensitivity and specificity, and diagnosis. A total of 234 articles were retrieved for analysis. Additional articles were identified by review of the references cited in these publications. Back to Top   

Introduction

Prostate cancer has become the most common type of cancer among men, and is the second leading cause of cancer deaths in males.¹ However, because it occurs primarily in older men, prostate cancer is the 21^st leading cause of years of life lost. In 1999, approximately 179,300 men in the United States were diagnosed with prostate cancer and approximately 37,000 deaths were attributed to this disease. The lifetime risk for clinical prostate cancer among men in the United States is approximately 10%; approximately 3% die of this disease. Major risk factors are age, family history, race, and possibly dietary fat.² 

Autopsy and cystoprostatectomy studies have shown a prostate cancer prevalence of 30% to 46% based on histologic examination. For men over age 50 years, the weighted average of prostate cancer prevalence based on autopsy studies is 30%.³ Approximately 20% to 25% of these cancers are believed to be clinically significant.⁴

Thus, the risk for a 50-year-old man with a 25-year life expectancy of having microscopic cancer is approximately 30%, of having clinically evident disease 10%, and of dying from prostate cancer 3%.⁵ The disparity between the 30% prevalence of histologic prostate cancer in men older than 50 years of age and the 3% lifetime risk of death shows the difficulty in distinguishing cancer that is destined to cause illness and death from indolent disease. Nevertheless, early detection is potentially important because the survival of patients diagnosed in early-stage disease is substantially better than that of patients diagnosed with late-stage disease.^6,7 Patients with symptomatic disease generally have late-stage cancer that has spread and is incurable. 

The main screening tests in use today for the early detection of prostate cancer are digital rectal examination (DRE) and measurement of the serum concentration of prostate-specific antigen (PSA). PSA is a glycoprotein with serine protease activity produced primarily by epithelial cells lining the acini and ducts of the prostate gland. PSA is secreted into the lumina of the prostatic ducts and is present in high concentrations in seminal fluid. Plasma concentrations are normally low but are increased by conditions that disrupt normal prostate structure and function (ie, inflammation, infection, hyperplasia, primary and metastatic cancer). Androgens regulate expression of the PSA gene.

The Food and Drug Administration (FDA) approved the PSA test in 1986 to monitor disease status of patients with prostate cancer, and in 1994 to aid in the detection of prostate cancer in men aged 50 years and older. Use of the PSA test for the diagnosis of prostate cancer, either in response to symptoms or for screening, increased dramatically beginning in 1988.⁸

Transrectal ultrasonography is generally reserved for further examination of patients who have abnormal results on DRE or PSA and to guide biopsies. Neither ultrasonography nor transrectal needle biopsy are recommended for screening.  Back to Top   

Principles of Screening

Screening  constitutes the use of laboratory tests, physical examination, or imaging modalities performed on asymptomatic patients with the intent of identifying subclinical disease. Early detection represents discovery of a condition or disease before obvious signs or symptoms have appeared; in patients with cancer this would imply the detection of localized disease. Screening can be further subdivided into mass screening  or individualized screening.⁹ The former is conducted with little regard for the risk profile of the individual patient. Most physicians are involved in the latter, which consists of recommending screening tests in the context of an ongoing patient-physician relationship.

The sensitivity  and specificity  of a particular test help to establish its effectiveness. Sensitivity equals the proportion of the disease population who have a positive test (true-positive rate). The specificity of a test equals the proportion of healthy patients who have a negative test (true-negative rate). Patients and clinicians are often more interested in the positive predictive value of a test, which equals the proportion of patients with a positive test result who actually have the disease. The relative value of cancer screening tests is also particularly dependent on the predictive value of a negative test result. Back to Top   

Criteria of Effective Screening Tests

For a screening test to be effective, certain criteria should be fulfilled, including the following⁹:

1. The disease must constitute a significant public health problem (common, with significant morbidity and mortality).
2. The disease or condition should have a readily available and acceptable treatment, and the potential for cure must be greater among screen-detected patients.
3. The screening test must have appropriate sensitivity, specificity, and positive predictive value (capable of detecting a sufficiently high proportion of cancer in the detectable preclinical phase).
4. The screening test should be acceptable to the patient and society.
5. There must be demonstrable improved health outcomes related to screening.
6. The screening procedure should have a reasonable cost; adequate resources and health services should be available to accomplish the screening and to provide the necessary interventions triggered by a positive test result.

It should also be noted that such tests should have sufficient accuracy and reproducibility in the field to ensure transferability across test sites. The degree to which prostate cancer screening tests fulfill criteria 2, 3 and 5 is controversial, leading to different specific policy recommendations from various organizations   (Table 1),  although all groups agree that the testing process should be conducted within the context of an informed patient-physician relationship. Recently, a task force of the American Urological Association published a best practice policy on the use of PSA testing.¹⁰ This policy states that "the decision to use PSA for the early detection of prostate cancer should be individualized. Patients should be informed of the known risks and the potential benefits." Back to Top   

Variables That Confound Assessment of Screening Tests

Several biases are inherent in the conduct of screening tests that can impact on apparent survival measures, thus affecting valid assessment of screening test effectiveness.⁹ In particular, lead time bias  makes the assessment of mortality improvements difficult. Early detection of cancer creates a backward shift in the starting point for measuring survival (earlier diagnosis), which may artificially increase incidence and lengthen survival. 

Autopsy studies have revealed that at least 30% of men who die have latent prostate carcinoma. This rate is much higher than the mortality rate (3%) attributable to prostate cancer. Screen-detected incidental cancers represent length bias. Individuals with more slowly progressive disease will tend to be detected. Length bias increases the incidence of early-stage disease and lengthens apparent survival, but has no effect on mortality rates or advanced-stage disease. 

People who agree to be screened are a self-selected group who may be more aware of the disease in question and more health conscious. Selection bias can occur whenever the group actually screened differs from the potential population of individuals to be screened. This bias also can cause apparent increases in survival of individuals with screen-detected cancers. Inadvertent misclassification of the cause of death or attribution bias can occur when a screen-detected abnormality is labeled as "cancer" on the patient's chart when in fact this abnormality would never have been clinically diagnosed in the absence of screen detection.

Because of these biases, case survival cannot be used to assess the effect of screening on mortality. Rather, prospectively determined mortality from the disease over a follow-up period beginning with randomization should be used. Also, one generally cannot make valid comparisons by comparing people screened with those who were unscreened in the past. The only way to determine the degree of benefit without bias is by comparing people offered screening with a group of truly comparable people who are not offered screening.

Some common methodologies used in observational epidemiology, particularly case-control and cohort studies, are sometimes used to evaluate screening. Valid application of these approaches requires that screening has been in place in a community for a sufficient length of time for a benefit to be detectable if it does occur. This period for PSA is probably just now approaching. Case-control studies have limitations because it can be difficult to differentiate a screening test from a diagnostic test for prostate cancer, and this imprecision in classification can have a major impact on the results of such studies.¹¹ Back to Top   

National Trends in the Epidemiology of Prostate Cancer

Proponents of the benefits of PSA screening have pointed to recent trends in prostate cancer incidence and mortality as evidence of its effectiveness. Based on data obtained from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI), age-adjusted rates for prostate cancer incidence increased significantly in the late 1980s, peaked in 1992, and then declined through 1996.¹² Age at diagnosis for whites began trending downward after the introduction of PSA screening. Stage at diagnosis also exhibited a downward shift to more organ-confined and less metastatic disease. An increase in the incidence of moderately differentiated tumors   (Gleason score 5 to 7) appears to be driving the overall incidence trend.¹³ After 1991, the incidence of well-differentiated tumors is decreasing faster than tumors with higher grades. Blacks exhibited similar trends but with a 1-year lag time, although they experienced a relative increase in high-grade, poorly differentiated disease. These findings confirm those of smaller regional studies.^9,14,15

Prostate cancer mortality increased an average of 1% per year between 1973 and 1990. Since 1990 the prostate cancer death rate in the United States has fallen an average of 1.1% annually, the decrease totaling 6.7% from 1991 to 1995.¹³

These changes in incidence are consistent with the introduction of a successful screening test that detects slower growing tumors and with an effect of lead time bias due to early detection of prostate cancer beginning in the late 1980s and early 1990s.¹⁶ Some of the increased incidence of localized stage disease may be due to length bias. The decrease in early-stage cancer in later years also suggests that lead time bias has occurred. The effect of lead time bias is further supported by the fact that the increase in early-stage disease was followed by a decrease in advanced-stage disease. 

However, other factors also may be contributing to these trends. For example, the increase in moderately differentiated tumors actually began in 1986 prior to widespread use of PSA testing. Changes in treatment practices also may be confounding the view of mortality. In the late 1980s and early 1990s the use of gonadotrophin-releasing hormone analogues and androgenic receptor blockers became prevalent, superceding the use of castration therapy or estrogen supplements. This change in treatment patterns could have contributed to the recent declines in mortality rates for prostate cancer.

Other factors also could have contributed to the shift in the tumor grade distribution before 1992, including an increase in the radical prostatectomy rate, a decline in transurethral resection (TURP) rates for benign prostatic hyperplasia (BPH), and an increase in biopsy rates. The changes in prostate cancer mortality observed since the introduction of PSA testing in the general population are also consistent with the hypothesis that a fixed percent of the rising and falling pool of recently diagnosed patients who die of other causes may be mislabeled as dying from prostate cancer (cause-of-death misclassification or attribution bias).¹⁷ Back to Top   

Effectiveness of Tests for Early Detection

Digital Rectal Examination (DRE).  Palpation of the posterior aspect of the prostate gland via DRE is intended to identify abnormalities, including nodules or asymmetry, which may indicate the presence of cancer. The use of DRE as a screening tool for early detection is limited because small tumors and those deep within the gland may not be detected, while larger, more readily palpable cancers are less likely to be confined to the prostate. In the pre-PSA era, only 33% of men with DRE-detected prostate cancer had tumors that were pathologically organ-confined.¹⁸ Abnormal results on DRE increase the odds of extracapsular disease 3- to 9-fold.³

In screened (not referred) populations, the detection rate of prostate cancer by DRE ranges from 0.2% to 2.2%, with positive predictive values of 17% to 34%.¹⁹ In population-based and volunteer studies, DRE had positive predictive values of 15% to 29%, with detection rates of 1.5% to 2.2%.³ Despite the limitations of DRE, this technique detects some cancers that occur in individuals with false-negative PSA measurements. In one recent large prospective trial, DRE detected 17% of cancers that would have been missed based on a PSA cut-off of 4 ng/mL. 

Two case control studies have reached conflicting results on whether screening DREs prevent advanced or fatal prostate cancer.^20,21 Back to Top   

Prostate-specific Antigen (PSA). A PSA value of 4 ng/mL is the standard threshold, which if exceeded, triggers further diagnostic investigation. In studies of men with prostate cancer, about 75% have PSA concentrations >4 ng/mL.²² However, this means that 20% to 30% of tumors will be missed when PSA is used alone. PSA values between 4 and 10 ng/mL are associated with a 1.5- to 3-fold increase in the risk of localized prostate cancer, and a 3- to 5-fold increase in the risk of extracapsular disease.^3,23 Approximately 50% of prostate cancers associated with PSA concentrations in this range are not organ-confined.²⁴ PSA concentrations more than 10 ng/mL further increase the risk of extracapsular malignancy. 

Because PSA elevations are not specific for prostate cancer, the PSA test has a high false-positive rate when used as a screening tool. On initial screening, 8% to 15% of men will have a PSA >4 mg/mL, and 11% to 34% of these men (1.5% to 4.1% of the screened population) will have a positive biopsy.²⁵ Current data suggest that the specificity of the PSA test is no more than 90%. In the American Cancer Society-National Prostate Cancer Detection Project, about 13% of PSA measurements each year exceeded 4 ng/mL, with a sensitivity of 70% and a specificity of 90%.²⁶ Specificity is lower in cohorts of men with BPH.²⁷ In prospective studies, the positive predictive value of PSA screening in asymptomatic men is roughly 25% to 33%, which means that only 1 out of every 3 or 4 men with PSA values >4 ng/mL actually have prostate cancer; two thirds or more are false-positive results.^22,28-30

In addition to a large number of false-positive results, PSA potentially may detect a high number of clinically insignificant tumors. It is not established at what point a prostate tumor produces sufficient PSA for the elevation to be detectable, nor whether this increase is associated with the biological potential to progress and metastasize. Based on radical prostatectomy case series, tumors with a volume of 0.5 to 1.9 mL may produce sufficient PSA to elevate plasma concentrations above 4 ng/mL and begin to manifest as extraprostatic disease.^31,32 One autopsy study showed that PSA levels are consistently elevated only when tumor volume exceeds 1 mL.³³  However, men with an otherwise normal prostate who are found to have prostate cancer detected mainly on PSA testing (stage T1c) have tumors that appear to be "clinically significant" in that their average volume is approximately 1.5 mL, and after radical prostatectomy approximately 25% of specimens have positive surgical margins.³⁴

Most screening studies using PSA have detected primarily pathologically organ-confined prostate cancer (62% to 71% of patients).^35-38 However, even small tumors (stage T1a; see   Table 2) that were well differentiated have been shown to be potentially dangerous in patients with a life expectancy of 15 years or more.³⁹

While reduction in stage T3 tumors was noted in one large screening series in men undergoing serial screening, this reduction was not seen in men with initial PSA values between 4 and 10 ng/mL, the population most expected to benefit from serial screening. On the other hand, approximately one third of cancers found through early detection efforts with PSA and treated surgically have evidence of extracapsular spread, poorly differentiated histology, large tumor volume, or distant metastases.^35,39,40  Thus, only a minority of prostate cancers that are detected as a result of PSA measurement and are treated surgically have been considered clinically insignificant.^41,42

This stage shift is impressive compared with historical controls (24% metastasis and 60% locally confined versus 2% metastasis and 77% locally confined). Only 10% to 15% of screen-detected prostate cancers have characteristics similar to prostate cancer in cystoprostatectomy specimens.³⁵ About 16% of cancers were judged to be insignificant, and an additional 10% were classified as minimal disease in a series of 157 stage T1c (biopsy-detected) prostate cancers treated with radical prostatectomy.
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Combined Use of DRE and PSA. Although comparison between the effectiveness of DREs and that of PSA measurement against a reference standard are lacking, PSA has a greater sensitivity but lower specificity than DRE.⁴³ Evidence from uncontrolled studies suggests that a combination of DRE and PSA measurement improves the overall rate of detection when compared to the detection rate of either test alone

On a prevalence screen, PSA detects prostate cancer in about 2% to 2.5% of men older than 50 years compared with a rate of about 1.5% using a DRE.⁴⁴ The PSA assay detects about one third of diagnosed cancers in asymptomatic men that are missed by DRE, whereas DRE detects about 20% of those missed with PSA. 

In studies employing both DRE and PSA, about 25% of screened men require further assessment, but no more than 4% will be diagnosed with cancer. This value may be significantly lower (perhaps as low as 1%) in an unselected population.³ In studies of early detection among volunteers and that defined the detection rate and positive predictive values, the proportion of patients with abnormal results on either DRE or PSA measurement was 18% to 26%; overall cancer detection rates were 3.5% to 4%. If either test result was abnormal, the positive predictive value varied from 15% to 21%. If both tests were abnormal, positive predictive values varied from 38% to 50%.^22,43,45,46 These detection rates may be higher than those obtained in men who are randomly selected.⁴⁷ 

Efforts to Enhance PSA Specificity

Because there is considerable overlap in PSA concentrations between men with cancer and those with BPH, the PSA test has a high false-positive rate when used as a screening tool. Because neither BPH nor the presence of lower urinary tract symptoms are independently associated with the risk of prostate cancer, their presence increases the likelihood that an elevated PSA level is a false-positive result.²² This has led to several efforts to increase the specificity of PSA testing.

PSA Density (PSAD). This value represents the quotient of serum PSA divided by the volume of the prostate gland as measured by transrectal ultrasonography (TRUS). This adjustment attempts to correct for the fact that PSA concentrations are elevated in proportion to the volume of BPH in men without prostate cancer and may help differentiate benign from malignant disease. Initial studies suggested that a PSAD of 0.15 may discriminate between patients with BPH and those with prostate cancer, particularly in those men with intermediate PSA values of 4 to 10 ng/mL.^48-51 Other investigators were unable to confirm that PSAD offered any advantage over PSA alone.^52-55 Some variance can be expected based on the ability to accurately determine prostate volume by TRUS. Additionally, studies that apparently showed advantages of PSAD over PSA may be biased because cancers tended to occur in smaller glands in these studies.⁵⁶

Other investigators have studied PSA transition zone density (PSA-TZ) (in which the PSA value was divided by the TZ volume of the prostate), again with disparate results.^57-62 The PSA-TZ determination is predicated on findings that PSA in the serum is strongly correlated with the TZ volume but not the peripheral zone volume and also that the TZ is the nearly exclusive site of BPH development. 

Because of the potential for bias occurring based on gland size, some recent studies stratified results based on prostate size and found that volume-specific endpoints may improve the discrimination of PSAD-type measurements.^63,64 Nevertheless, because TRUS would be required in all men undergoing PSA to employ these approaches, they are not widely used. 

PSA Velocity.  Another approach to enhancing PSA specificity is to measure the rate of change in PSA over time. A rate of increase of 0.75 to 0.8 ng/mL per year observed via a minimum of 3 measurements over a 2-year period may help differentiate between cancer and benign disease.^65-67  Results of another study suggest that an annual rate of change of 1 ng/mL signifies the requirement for repeat biopsies in men with initially negative biopsy results and PSA values between 4 and 10 ng/mL.⁶⁸ High-risk patients also might qualify for use of this adjustment parameter.

Age- and Race-specific PSA Reference Ranges. Serum PSA concentrations increase with both the presence of BPH and advancing age; the latter correlation largely reflects increasing prostatic volume. Such changes were not considered when the standard PSA reference range (0-4 ng/mL) was originally established. Age-specific reference ranges are intended to improve the sensitivity for detecting prostate cancer in younger men (at the expense of increased biopsies), while improving the specificity of prostate cancer detection in older men (at the expense of missed cancers). The original age-specific PSA reference range was established primarily in whites to yield 95% specificity in detecting prostate cancer. A widely quoted age-specific range for blacks is slightly higher, but is based on achieving 95% sensitivity.⁶⁹ Applying this criteria to white patients would yield a PSA value of 3.5 ng/mL as a cut-off for anyone over 50 years of age. Nevertheless, among biopsied men without histologic evidence of prostate cancer, blacks have significantly higher PSA concentrations (and PSA density) than similarly aged white men.⁷⁰ Benign prostatic tissue of black men appears to contribute more PSA than does benign prostatic tissue of white men.⁶⁶  Long-term outcome studies are necessary to determine whether the use of lower PSA cut-offs would result in favorable shifts in cancer stage and grade, and a reduction in racial differences in prostate cancer mortality rates.⁷²

Subsequent reports on the relative value of using age-specific ranges have yielded conflicting results.^73-76 A recent large-scale analysis concluded that although using an age-specific reference range increases the positive predictive value of the PSA test and results in fewer unnecessary biopsies, the lower sensitivities even in combination with DRE result in significantly fewer cancers detected, and such use was not advisable.⁷⁷ 

Neither PSA assay manufacturers nor the FDA currently recommend age-specific PSA reference ranges.

Molecular Forms of PSA. The enzymatically active form of PSA is produced by the action of human glandular kallikrein 2 (hK2), which is also expressed by prostatic epithelial cells. Most circulating PSA (80%) is complexed with a ₁-antichymotrypsin (ACT); smaller amounts are complexed with a ₁-protease inhibitor, protein C inhibitor, and a ₂-macroglobulin. Free PSA accounts for a smaller amount of circulating PSA. For reasons that are not understood, free PSA accounts for a larger proportion of the total amount in men without carcinoma, whereas PSA-ACT comprises a larger proportion in patients with cancer, and improves the ability to distinguish benign conditions from cancer.^78-81 Using a cut-off of 20% to 25% free PSA in patients aged 50 to 75 years with a normal DRE and PSA values of 4 to 10 ng/mL detects 95% to 97% of cancers and eliminates 13% to 20% of biopsies.^82,83 In men with a normal DRE and PSA values between 2.6 and 4 ng/mL, a %free PSA cut-off of 0.27 resulted in a sensitivity of 90% and a specificity of 18% for cancer detection. Using the %free PSA can also reduce the number of unnecessary biopsies performed in men with total PSA values of 3 to 10 ng/mL, but the optimal cut-off point is not established; values ranging from 14% to 28% have been suggested.⁸⁴

Interpretation of free PSA values may be affected by the presence of prostatitis, and the validity of measurements can be affected by pre-analytical handling and storage, and assay variance.^85,86 The greatest utility of free PSA presently may be in patients whose total PSA is in the range of 4 to 10 ng/mL but who have a normal DRE and negative biopsy result.⁸⁷  A more recent attempt to increase the specificity of PSA values is the measurement of "complexed PSA."⁸⁸ Back to Top   

Effectiveness of Treatment

The availability of effective treatments that improve outcome in screened patients is necessary for screening tests to be effective. Currently, evidence from controlled clinical trials is lacking that aggressive treatment (with radical prostatectomy or radiotherapy) for men with prostate cancer that appears to be localized to the prostate gland improves outcomes. In general, histologic grade is the strongest prognostic factor, although the grade from biopsy specimens differs from surgical specimens in 30% of cases. Tumor volume that exceeds 0.5 mL (a characteristic of approximately 20% of autopsies) has been considered clinically significant, but it remains uncertain whether tumor volume, adjusted for grade, is an independent predictor of disease-specific survival.⁸⁹ 

In the absence of controlled trials assessing mortality, several observational studies have examined the outcomes of men with clinically localized prostate cancer treated with different modalities. An overview of observational studies indicates that the 10-year disease-specific survival rate is >80% for men with prostate cancer of low to moderate grade who do not receive active treatment ("watchful waiting" or "expectant management").⁹⁰ The largest study found that the degree of differentiation of the tumor was the best predictor of outcome, regardless of treatment.⁹¹ In this study, most of the cancers were detected in the pre-PSA era. Well-differentiated tumors had the same outcome regardless of treatment. Surgical intervention improved outcome in patients with moderately differentiated tumors. Results of this kind of study may favor surgery, because (biopsy) SEER grade and stage data are based on clinical data in the absence of surgery, and definitive pathological data are determined following surgery. Thus, tumors that are treated conservatively (nonsurgically) are often undergraded. Although histological features are highly predictive of survival in men with localized prostate cancer, co-morbidities are nearly as important ⁹² 

In 7 studies of men with palpable, clinically localized cancer who had been treated since 1980 and who had received expectant management, the 10-year disease-specific survival rate was lower for expectant management (84%) than for radical prostatectomy (93%) but was lower still for radiotherapy (74%).⁹³ The development of metastases and death from prostatic cancer was 50% lower in men who underwent radical prostatectomy than in those followed expectantly.

In a widely quoted Swedish study involving 223 men (mean follow-up 12.5 years) with prostate cancer, mortality related to cancer was 10%, whereas 66% died from other causes.⁹⁴ Ten-year metastasis-free survival corrected for deaths from other causes was 83%. However, this study included primarily older patients (mean age 72 years) with small, well-differentiated tumors. Notably, even in this well-selected group of patients (who should have done well), after 10 years, 13% had died of cancer and another 50% had developed progressive disease. Finally, in another retrospective study, men with clinically localized tumors that were well-differentiated or moderately differentiated had a crude 10-year survival of 78%; 40% of deaths in this group were caused by prostate cancer.⁹⁵

Taken together, the results of these trials suggest that an opportunity exists for active treatment to reduce mortality in patients with clinical localized prostate cancer.

Additionally, results of randomized, prospective, controlled clinical trials suggest that the early initiation of adjuvant hormonal therapy with radiotherapy (with or without androgen receptor blockade) improves survival in patients with stage T3-4 prostate cancer and also appears to benefit patients with either node-positive prostate cancer or metastatic disease.^96-99 These findings may expand the potential pool of men expected to benefit from the use of PSA screening. Back to Top   

Randomized Trials Underway on Prostate Cancer Screening and Treatment

It is anticipated that the following trials will provide more definitive evidence regarding the value of prostate cancer screening with DRE and PSA.

Treatment. Two important prospective randomized clinical trials, one in Scandinavia and one in the United States, are evaluating the efficacy of treatment with radical prostatectomy compared with expectant management. The Scandinavian trial, which restricts enrollment to men with well or moderately differentiated tumors, has neared completion of accrual and an interim analysis is planned for approximately 2005. In the United States, the Prostate Cancer Intervention Versus Observation Trial (PIVOT) has enrolled more than half of the 1050 patients needed with clinically localized prostate cancer who are candidates for radical prostatectomy. Conducted under the auspices of the Veterans Administration and the NCI, the main endpoint is survival. Anticipated completion is 2008.

Screening Three prospective randomized trials on the effects of screening on mortality are underway. The Canada Quebec trial is a population-based trial that started in 1988. A total of 46,193 men aged 45 to 80 years were identified through electoral lists as residing in the area of Quebec; 30,956 were invited to be screened, of which 7155 accepted and were screened. In the control group, 982 men were screened. The cut-off is a PSA level of 3 ng/mL; rescreening is annual. Intention-to- treat analysis after a 10-year period found no reduction in mortality.

The US Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening trial is based on volunteers aged 55 to 74 years who sign a consent form to be randomized (n=74,000); half will be randomized to receive annual PSA and DRE screening to a total of 4 screens and half to usual care in the community. PSA cut-off is 4 ng/mL. Results are expected by 2006.

The European Randomized Study for Screening for Prostate Cancer is a multicenter trial initiated in 1994 that plans to enroll up to 239,000 men in 10 different countries. Method of recruitment, age of the enrollees, PSA cut-offs and the frequency of screening will vary somewhat among the centers. More than two thirds of the target number was enrolled through July 1998; expected completion of the trial is 2008. In the Finnish arm of the trial, more than 5,000 participants have been screened; PSA levels exceeded 4 ng/mL in 8.5% of men aged 55 to 69 years. The cancer detection rate was 2.1% with a positive predictive value of 27%. More than 80% of the cancers were localized and well or moderately differentiated.¹⁰⁰ 
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Potential Harm Associated with Screening and Treatment 

Clearly, PSA testing identifies cancer at an earlier stage of disease. Potentially curative treatments include radical prostatectomy, cryosurgery, external beam radiation therapy, or brachytherapy. The main potential harm associated with screening for prostate cancer is overdiagnosis and subsequently treating men with indolent disease. The possible harms associated with screening must consider the psychological consequences of positive screening results or an actual cancer diagnosis, and the reality of false reassurance with negative biopsy results.^101,102 Perhaps more important are the morbidity and mortality associated with the cascade of procedures from diagnosis to staging to treatment. The complications of radical prostatectomy include a low mortality risk (0.2% to 0.4%), but considerable morbidity affecting the quality of life may be associated with this surgery (incontinence and erectile dysfunction) or from radiation (bowel dysfunction and rectal bleeding).

Cost-effectiveness

The cost of a one-time prostate cancer screening of US men over 50 years of age has been estimated at between $12 and $28 billion.^44,103 Insufficient data are available to formally model serial screening or high-risk groups. Assuming a benefit for aggressive treatment, one cost-effectiveness analysis (model) for one-time DRE and PSA measurement suggested that men aged 50 to 69 years are more likely to benefit at a reasonable cost.¹⁰⁴ A wide range of cost per year of life saved has been published depending on the data utilized in the calculation ($8,400 to $145,600).^105-107 A more definitive model of the net cost of mass screening programs for prostate cancer will depend on the results of ongoing randomized trials for screening and treatment.

Informed Consent

Men in the US lack knowledge about prostate cancer and early detection, and patients who undergo PSA screening often are unaware of its risks and benefits.^108,109 Several US trials have demonstrated that providing basic information about the pros and cons of PSA testing, in written or video form, can lead to more informed decision-making, which reduces patient interest in PSA testing and leads to fewer tests being performed.^110-112 Patients given information about PSA screening and prostate cancer are more likely to be interested in screening if they have a family history of prostate cancer, are younger, or otherwise consider themselves susceptible to developing prostate cancer.¹¹³ Back to Top   

Summary and Conclusion

Measurement of PSA is the most sensitive noninvasive test available for early detection of prostate cancer, and its use may lead to earlier diagnosis of aggressive disease. The shifts in age at diagnosis and in the stage of cancer detected, and the changing pattern of prostate cancer incidence and mortality are perhaps early signs of the success of PSA screening, although alternate explanations exist.

Combining the use of PSA with DRE increases the early-detection rate in asymptomatic individuals. Indirect measures (a higher survival rate for patients with early-stage disease; types of tumors detected by PSA more likely to be early-stage disease; PSA-detected tumors seem to have features associated with increased risk for progression) suggest a possible benefit to PSA screening. However, one cannot infer that merely detecting prostate tumors with certain histopathological features improves outcomes (surrogate marker). Instead, evidence should be derived from clinical trials of patients with screen-detected cancers, as screen-detected cancer may be more likely to respond to existing treatments than clinically diagnosed cancers. The ratio of cumulative incidence (which is increasing because of early detection efforts) to mortality rate (which is relatively stable or slightly declining) suggests that most cases of prostate cancer that are being detected with current methods are not fatal. However, the decline in the incidence of distant-stage disease suggests that use of PSA testing may lead to a sustained decline in prostate cancer mortality. 

Given the "current lack of definitive evidence supporting or refuting the effectiveness of screening as a method to reduce the morbidity and mortality from prostate cancer, guidelines must distinguish public policy from individual clinical practice."¹¹⁴ On an individual basis, testing offers an uncertain hope. Some individuals who undergo screening with DRE and PSA will likely benefit; others will not, and still others may experience harm. The relatively long doubling time (on average) of early prostate cancer of 3 to 4 years or more indicates a relatively good prognosis for many men with this cancer, even without early detection and treatment. Reduced PSA test specificity in men with BPH leads to high rates of prostatic biopsy and its attendant illness and costs.

The launching of mass screening programs for the early detection of prostate cancer is premature. However, in the absence of solid evidence of benefit, one reasonable approach to screening at the individual level is to involve the patient in decisions about whether to perform a PSA test. Thus, "offering" PSA testing must be accompanied by informed discussion within the context of an ongoing patient-physician relationship. This is to be distinguished from the use of PSA testing for the purpose of "mass screening." The current conflicting recommendations reflect "differences in the level of evidence required to make a positive recommendation rather than different interpretations of the results of existing studies."³

Physicians should be aware of the uncertainties in the key variables that influence early detection decisions and the tradeoff of potential benefits for known risks before they and their patients make a screening decision. Lack of proof of net benefits from early detection with DRE and PSA and the potential for serious attendant harm mandate a higher level of informed consent than exists for most "simple" diagnostic tests. Concepts that must be explored with the patient include: (1) The long-term ramifications of screening; (2) the relatively high probability of further evaluation and biopsy with positive results; and (3) potentially difficult decisions that may arise about using treatments that are associated with considerable morbidity and uncertain benefits (at this time) if cancer is discovered. Back to Top 

RECOMMENDATIONS (Adopted AMA Policy)

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA Policy at the June 2000 Annual Meeting. 

The AMA believes that:

1. The launching of mass screening programs for the early detection of prostate cancer is premature at this time.
2. All men who would be candidates for and interested in active treatment for prostate cancer should be provided with information regarding their risk of prostate cancer and the potential benefits and harms of prostate cancer screening, sufficient to support well-informed decision making. 
3. Prostate cancer screening, if elected by the informed patient, should include both prostate-specific antigen testing and digital rectal examination. 
4. Men most likely to benefit from tests for early detection of prostate cancer should have a life expectancy of at least 10 years and include:

• Men 40 years of age or older of African American descent
• Men 40 years of age or older with an affected first-degree relative
• Men 50 years of age or older 

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Table 1. Current Guidelines on Prostate Cancer Screening

Organization	Year	Guideline
American Cancer Society	1997	Both prostate-specific antigen (PSA) and digital rectal examination (DRE) should be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy and to younger men who are at high risk.
American Urological Association	1997	Both PSA and DRE should be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy, and to younger men who are at high risk
American College of Radiology	1997	Both PSA and DRE should be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy and to younger men who are at high risk. Information should be provided to patients regarding potential risks and benefits.
US Preventive Services Task Force	1995	Routine screening for prostate cancer with DRE, serum tumor markers (eg, PSA), or transrectal ultrasound is not recommended.
American College of Physicians	1997	Rather than screening all men for prostate cancer as a matter of routine, physicians should describe the potential benefits and known harms of screening, diagnosis, and treatment; listen to the patient's concerns; and then individualize the decision to screen. The College strongly recommends that physicians help enroll eligible men in ongoing clinical studies.
American College of Preventive Medicine	1998	Recommends against routine population screening with DRE and PSA. Men aged 50 or older with a life expectance of greater than 10 years should be given information about the potential benefits and harms of screening and limits of current evidence and should be allowed to make their own choice about screening, in consultation with their physician, based on personal preferences. Methods and tools for helping patients review this information are available, however the ACPM recommends further research be conducted in optimizing the process of patient education and informed consent.
Canadian Task Force on the Periodic Health Examination	1994	Recommends excluding PSA as a routine screening measure based on poor predictive value and uncertain balance of harms and benefits.

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Table 2. Prostate Cancer Tumor Staging (TNM System)

Primary Tumor (T)	Definitions
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Clinically inapparent tumor not palpable or visible by imaging
T1a	Tumor-incidental histologic finding in 5% or less of tissue resected
T1b	Tumor-incidental histologic finding in more than 5% of tissue resected
T1c	Tumor identified by needle biopsy (eg, because of elevated PSA)
T2	Palpable tumor confined within prostate
T2a T2b	Tumor involves half of a lobe or less Tumor involves more than half of a lobe, but not both lobes
T2c	Tumor involves both lobes
T3	Tumor extends through the prostatic capsule
T3a T3b T3c	Unilateral extracapsular extension Bilateral extracapsular extension Tumor invades seminal vesicles
T4	Tumor is fixed or invades adjacent structures other than seminal vesicles
T4a	Tumor invades external sphincter and/or bladder neck and/or rectum
T4b	Tumor invades levator muscles and/or is fixed to the pelvic wall
Lymph Node (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2	Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension
N3	Metastasis in a lymph node more than 5 cm in greatest dimension
Distant Metastasis (M)
MX	Presence of distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
M1a M1b M1c	Nonregional lymph nodes Bone Other sites

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108. O Dell KJ, Volk RJ, Cass AR, Spann SJ. Screening for prostate cancer with prostate-specific antigen test: are patients making informed decisions? J Fam Pract.  1999;48:679-681.
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112. Volk RJ, Cass AR, Spann SJ. A randomized controlled trial of shared decision making for prostate cancer screening. Arch Fam Med.  1999;8:333-340.
113. Wolf AM, Philbrick JT, Schorling JB. Predictors of interest in prostate-specific antigen screening and the impact of informed consent: what should we tell our patients? Am J Med. 1997;103:308-314.
114. Burack RC, Wood DP. Screening for prostate cancer. Med Clin North Am.  1999;83:1423-1442.

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Resolution 511 (I-99)

Resolution 511, introduced by the American Urological Association and the American Association of Clinical Urologists and referred to the Board of Trustees at the 1999 Interim Meeting asks:

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Gleason Score
The Gleason score (range 2-10) is obtained by identifying the two predominant architectural patterns in the biopsy and assigning a grade of 1 (well differentiated) to 5 (very poorly differentiated or undifferentiated) and then adding the two numbers. Tumors with a Gleason score of 2-4 generally have lower biologic aggressiveness; those with a score of equal to or greater than 7 are biologically aggressive.
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