Population Screening for Prostate Cancer and Early Detection in High-risk African American Men*

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Population Screening for Prostate Cancer and Early Detection in High-risk African American Men*

Chapter

1

Judd W. Moul Urology Service, Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307-5001, and Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA

Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and approximately 13% of all cancer deaths.1 Nearly one of every six men will be diagnosed with the disease at some time in their lives.1 In 2002 alone, an estimated 189 000 US men were diagnosed with prostate cancer, and more than 30 000 will die of the disease.1 Despite the fact that population-based screening for prostate cancer has yet to be definitively proven or disproved to affect the disease-specific mortality, this summary explores changes in the ‘PSA Era’ (defined as the time in the USA when the prostate specific antigen (PSA) screening test came into widespread clinical use) and the prospects for targeted screening of certain groups of individuals who may be at particular risk of developing prostate cancer, namely African American men.

PROS AND CONS OF POPULATIONBASED SCREENING IN GENERAL Early detection for prostate cancer has been practiced for many years in the form of the digital rectal examination (DRE). However, over the last 15 years with the advent of prostate specific antigen, or PSA, the topic of prostate cancer screening has become a hotly contested issue.2,3 Early detection may take the form of the population-based screening or case finding. In the early 1990s, the American Cancer Society (ACS), the American Urological Association (AUA) and other organiza-

tions advocated screening for the early detection of prostate cancer.4,5 These groups recommend a DRE and PSA test for men starting at age 50. Notably, however, other organizations had argued against screening, including the US Preventative Services Task Force, the American Academy of Family Physicians and the American College of Physicians.6,7 Several factors favor the use of screening for the early detection of prostate cancer. First, because patients do not experience symptoms during the early stages, they are unlikely to seek care until the disease has progressed. Second, improvements in detection methods have increased the prospects for identifying the disease in its early stages, when the cancer is still confined to the organ, and is more easily treatable and often curable. Third, early detection might mean the difference between life and death, as no cure has been found for the advanced disease. To be of value, screening must lead to treatment that has a favorable impact on prognosis. Catalona et al. were one of the first groups to examine this issue by comparing disease stages in patients with prostate cancer who had or had not undergone or had PSA screening.8 The screened group had a lower percentage of cases with advanced disease and no greater percentage with latent disease. The investigators concluded that screening reduces the incidence of advanced disease and implied that the death rate will ultimately decrease.8,9 Since these reports, there have been a multitude of studies documenting the changes in the epidemiology of prostate cancer in the ‘PSA-Era’.

*The opinion and assertions contained herein are the private views of the author and are not to be considered as reflecting the views of the US Army or the Department of Defense.

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PSA-ERA CHANGES SUPPORTING GENERAL SCREENING When an effective screening tool is introduced into a population, the following events should occur. There should be a transient increase in incidence owing to labeling of prevalent cancers. The cancers should be diagnosed in patients of a younger age. The cancer should be diagnosed at lower stages and there should be an apparent increase in disease-specific survival.10,11 As of 2002, PSA testing has arguably fulfilled these criteria, and many clinicians practice screening. Regarding the change in prostate cancer incidence, the SEER (Surveillance, Epidemiology and End Results Program of the National Cancer Institute) data as well as data from the Mayo Clinic and other sites document the change.12–16 Specifically, starting in 1989 and peaking in 1992, there was a marked rise, with a subsequent decrease of approximately 30%. These trends exemplify the Cull effect, that is, with the introduction of any screening tool into a population, there will be a rise in incidence, with a subsequent fall. This fall is because of the depletion of the prevalence pool of previously undiagnosed cases. The steady-state incidence of prostate cancer in the PSA-Era will eventually be a reflection of both patients aging, and entering into the pool, and those being removed from the pool as a result of dying, or being diagnosed with prostate cancer.12 It is unclear whether the incidence will decrease to prescreening levels, or remain higher than previous years.16,17 Current statistics from the SEER data indicate that the steady-state incidence in the PSA-Era has yet to be reached.1 Others have suggested that the fall in incidence is influenced by less aggressive screening by primary care physicians in response to data in the scientific and lay media that screening for prostate cancer does not effect morbidity and mortality.18,19 In the Department of Defense Center for Prostate Disease Research (CPDR) program, the incidence of new cases continues to be above prescreening levels and appears to have leveled off.20 The mean and median age of men at diagnosis has decreased significantly in the PSA Era. The introduction of age-specific reference ranges for PSA screening, first by Osterling et al., and subsequently by race and age by Morgan et al., have shown that prostate cancer, detection and subsequent treatment is an age-dependent process.21,22 The younger the patient is at the time of diagnosis, presumably, the earlier they are in the course of their disease. If curative-intent treatment is rendered at an earlier age, the more likely cure would occur. Chodak et al. have shown that men under 61 years of age had a statistically significant improved disease-specific survival.23 Smith et al. from our group have also shown that younger age at diagnosis is an independent predictor of better prognosis.24 Age greater than 65 years has been demonstrated to be an independent predictor of distant metastasis.25 Carter et al. have recently suggested that detection of prostate cancer in younger men is likely to lead to a decrease in prostate cancer mortality.26 In summary, there is strong evidence that, if the diagnosis of prostate cancer is made at a younger age, disease-specific mortality can be significantly reduced, and it

is now demonstrated that, in the PSA-Era, the age at diagnosis had decreased significantly. The decline in the age at the time of diagnosis from 72 to 69.4 years of age from 1990 to 1994 has been shown by the SEER data.18 From the SEER data and other literature, a leadtime of between 3 and 5 years is derived.13,15,18,27 In other words, with the aid of PSA, we are detecting cancers 3–5 years earlier than prior to screening. Thus the increase in survival (time of diagnosis to time of death) in the PSA-Era must be at least 3–5 years longer that the previous expected survival time to show any benefit in disease-specific survival with PSA screening. There has also been a significant stage migration in the PSA-Era. Most strikingly, the percentage of patients presenting with metastatic disease decreased from 14.1% and 19.8% in 1988 and 1989, respectively, to 3.3% in 1998 from our CPDR database.20 Before a survival benefit, a decrease in metastatic disease should be evident, which is clearly being shown on a national level by several studies.12–14,28 These findings are more impressive in light of the fact that no curative treatment exists for patients with metastatic disease. Similarly, we have also shown a statistically significant decrease in the incidence of clinical T3 and T4 disease. Again, demonstrating a stage shift from disease that can merely be managed, to disease that is amenable to cure. These T3 and T4 tumors, as well as T2 tumors, are most likely being diagnosed several years prior to when they would previously become evident. The advent of PSA testing is reclassifying these tumors as T1c, which is associated with decreased recurrence rates, and increased disease-specific survival, when compared to other clinical stages.29–31 The level of PSA at the time of diagnosis is a general surrogate of tumor volume or cancer burden. A decline in PSA levels over time is further evidence of stage migration to support screening. In our CPDR studies, the median PSA at the time of diagnosis decreased from 11.8 ng/dl in 1990 to 6.3 ng/dl in 1998.20 This is consistent with the findings of Vijayakumar et al. who have recently demonstrated a statistically significant drop in the PSA level of African American patients presenting with prostate cancer.32 Partin et al. have shown that the lower the pretreatment PSA prior to prostatectomy, the lower the chance of extracapsular extension, seminal vesical involvement and lymph-node metastasis.33 Moul et al. and many other investigators have shown that the PSA level is a significant contributor in determining the risk of recurrence after treatment with radical prostatectomy.34 Similarly, in patients treated with external beam radiation, the lower the level of pretreatment PSA, the greater the disease-free survival.29,35 Hopefully, this continued decrease in PSA at the time of diagnosis portends more successful treatment outcomes in the future. Most of the tumors diagnosed in the PSA-Era are not indolent tumors by traditional grade and Gleason criteria. Multiple studies including SEER have shown that moderately differentiated or Gleason sum 5–7 tumors predominate in the PSA-Era.12,13,36,37 One reason for the decrease in welldifferentiated tumors is the decrease in the number of

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transurethreal resection of the prostate (TURP) performed. It is established that tumors arising in the transitional zone (area resected with a TURP) have a significantly higher incidence of tumors with lower Gleason sum than tumors discovered in the peripheral zones by needle biopsy.38,39 Smith and Catalona have shown that 97% of the tumors detected through PSA screening are medically important (defined as palpable, multifocal or diffuse, and moderately or poorly differentiated).31 Other recent studies confirm that moderately differentiated or mid-Gleason grade tumors are clinically significant, with higher recurrence and diseasespecific mortality that lower grade tumors.23,40–42 Regarding survival, Gilliland et al. showed improved survival during a period of PSA screening in New Mexico using the SEER data.43 The SEER 5-year relative cancer survival rates for patients diagnosed in the following years groups: 1974–1977, 1980–1982 and 1989–1995 were 67%, 73% and 92%, respectively; each of these changes were statistically significant (P < 0.05). Etzioni et al. have determined that the improved survival is not due simply to PSA testing, even if one considers a very short lead time of 3 years.44 It is probably related to screening and more aggressive treatment. Nevertheless, our own data from CPDR also shows significant improvements in 5-year prostate cancer specific survival rates as the PSA Era has progressed.45 Specifically, for patients diagnosed between 1988 and 1991 at the Walter Reed Army Medical Center, the cancer specific survival was 81.7% compared to 92.5% for men diagnosed between 1992 and 1994 and 98.3% for men diagnosed between 1995 and 1998. This was based on a cohort of 2042 men and the cause of death was determined prospectively using the National Death Index, direct deaths certificate review and choice point commercial service (Fig. 1.1). Aside from these population and database trends, screening studies by Labrie et al.46 and Bartsch et al.47 suggest a benefit to population-based screening. Most notably, Bartsch et al. recently reported early results of the Tyrolean prostate cancer screening study in Austria.47 By aggressively offering screening to all men in the Tyrolean state of Austria between 1993

100 1995–98

Survival rate (%)

95 90 1992–94 85

5

and 1997, and testing two-thirds of eligible men between the ages of 45 and 75, they report a 42% decline in the diseasespecific mortality for prostate cancer compared to the rest of the county where PSA testing was not commonly practiced.

ARGUMENTS AGAINST POPULATION SCREENING Opponents of screening point to the potential for side effects from treatment, the possibility that some men will be treated unnecessarily, the economic burden on the health care system and the lack of definitive scientific evidence that the screening will reduce overall disease-specific mortality.19 Indeed, many men with prostate cancer do not die of the disease, whereas many other patients die of the disease despite our best efforts. No foolproof markers are currently available to differentiate these two groups. Therefore, a key objection to screening is that such efforts may uncover many cancers that, if left undetected, would never have caused morbidity or mortality; conversely, some cancers will cause death despite being detected by screening. Some observers have further recommended that screening should be avoided in men older than 70 or 75 years of age so as to reduce the detection of such ‘incidental cancers’ that are unlikely to affect life expectancy. Aside from the ‘true’ screening, or population-based screening controversy, case finding for prostate cancer using PSA and DRE is widely practiced. Case finding is the process of evaluating men with symptoms where the testing is for differential diagnosis of urinary tract or other disease. In this setting, PSA and DRE are standard tools that physicians must have at their disposal.48 The process of targeted screening for prostate cancer in a higher risk group of men, such as Blacks and those with a family history, could arguably, in my opinion, be considered similar to case finding. Recognizing that population screening for prostate cancer using PSA and DRE remains disputed to reduce the morbidity and mortality of the disease, authorities currently recommend that physicians and health care organizations provide the pros and cons as outlined above and let the well-informed patient decide. Many would argue that it would be wrong to mandate screening; however, it would be just as wrong not to offer the option of early detection tests for prostate cancer, especially for high-risk targeted groups, especially in light of aforementioned positive trends in the PSA-Era. Recently, the ACS and AUA have updated their prostate cancer screening to this effect.49,50 Most notably, the recommendations call for testing if the patient is undecided.49

80

SHOULD AFRICAN AMERICAN MEN UNDERGO SCREENING FOR PROSTATE CANCER?

1988–91

75 70 0

1

2

3

4

5

6

7

8

9

10

Time to death from prostate cancer (years) Fig. 1.1. Survival from prostate cancer by time period of diagnosis.

For African American men specifically, do we recommend population screening based on current knowledge of greater incidence, greater stages at diagnosis and worse outcome or do

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we wait for more definitive screening efficacy studies? I believe we have reasonable basis to recommend routine testing now using screening guidelines optimized for Black men.

RACIAL DIFFERENCES It has been widely recognized that there are observed differences in prostate cancers in White and Black men51–53 and our own studies in the equal access US military health care system are no exception.54 In 1995, we were the first to show that Black men with newly diagnosed prostate cancer had higher PSA values than White men, even after adjustment for age at diagnosis and grade and clinical stages of cancer.55 This study also documented that, even within the traditional clinical stage categories at diagnosis, Black men had significantly greater cancer volumes. Considering that the Black men were, on average, about 3 years younger than the White men, this tumor volume disparity was striking. In a more recent update with 226 cases, the higher cancer volume stage-for-stage in Black men persisted.56 What is accounting for the greater cancer burden in these Black men, who seemingly have equal access to screening as the White men? It could be that the Black men are not availing themselves to testing, have greater delay in diagnosis and larger tumors. We know that, in general, there has been less awareness of prostate cancer and less screening in the African American community.57 Data from Prostate Cancer Awareness Week consistently show that only about 5% of participants are Black despite the fact that 12% of the population as a whole is Black.58 On the other hand, is there a biologic factor, or factors, such as testosterone, that is making these tumors grow bigger more quickly? Studies in younger men have shown that Blacks had testosterone levels 10–15% higher than age-matched Whites.59 Furthermore, a more recent study has found genetic variation in the androgen receptor (AR) gene that may make the receptor more active in African American men.60 Specifically, the CAG polymorphic repeat in exon 1 of AR is shorter in Black men and theoretically could potentiate the effect of testosterone in prostatic cells. Alternatively, is it a combination of behavior and biology that is responsible for the observed differences? Despite not knowing the exact cause, what can we do now?

RACE-ADJUSTED GUIDELINES Working with the US military health care systems patients, our group has shown that Black men with newly diagnosed prostate cancer have higher serum PSA values than do Whites, even after correction for stage grade and tumor volume.55 In view of these findings, our group has also studied the ability of PSA to detect prostate cancer in both Caucasian and African American men and developed age-adjusted PSA reference ranges for maximal cancer detection.22 In this study, between January 1991 and May 1995, serum PSA concentration was

determined for 3475 men without clinical evidence of prostate cancer (1802 Caucasians, 1673 African Americans) and 1783 men with this disease (1372 Caucasians, 411 African Americans). PSA concentration was analyzed as a function of age and race to determine operating characteristics of PSA for the diagnosis of prostate cancer. Serum PSA concentration correlated directly with age for both Black and White men (r = 0.40, P = 0.0001 for Blacks and r = 0.34, P = 0.0001 for Whites). African American men had significantly higher PSA concentrations than Caucasian men (P = 0.0001). When sensitivity was plotted against 1-specificity, the area under the receiver operator characteristic (ROC) curve was 0.91 for Black men and 0.94 for White men, indicating that the PSA test was an excellent early detection tool. For comparison, the Papanicolaou smear for cervical cancer, which is an accepted clinical screening test, has an ROC value of 0.70. When we calculated age-specific reference ranges using identical methodology to Oesterling and colleagues in their 1993 study of primarily Caucasian patients from Olmstead County, Minnesota,21 we found very similar values for White men but higher values for Black men. These ranges were 0–2.4 ng/ml for black men aged 40–49, 0–6.5 ng/ml for men aged 50–69, 0–11.3 ng/ml for men aged 60–69, and 0–12.5 ng/ml for men aged 70–79. We then tested these new ranges in our group of Black men with prostate cancer to determine how these ranges would have performed, if they had been used to detect their cancers. Unfortunately, these markedly higher ranges would have missed 41% of the cancer (only 59% sensitivity). The reason these traditionally derived ranges performed so poorly is because they are simply the 95th percentile of values in the Black controls. Because there is more variability of PSA results in Blacks without the evidence of cancer, there is more skewness, which pushes the 95th percentile farther to the right (higher). This higher range, however, is not clinically useful. We, therefore, developed age-adjusted reference ranges for Black men with prostate cancer, selecting PSA upper limits of normal by decade in the men with prostate cancer by using the 5th percentile of PSA values. Only the lowest 5% of prediagnosis PSA values in the Black men with cancer are ‘normal’ and the remainder (95%) are above the normal (95% sensitivity). We refer to these ranges as the Walter Reed/Center for Prostate Disease Research age-specific reference ranges for maximal cancer detection (Table 1.1). They maximize sensitivity (cancer detection) without undue loss of specificity [false-positive/unnecessary transrectal ultrasound (TRUS)/ biopsy]. Reference ranges have been controversial especially for older men because they raise the ‘normal’ above 4.0 ng/ml. Advocates of screening have been concerned that ‘important’ cancers will be missed in these ‘older’ men who may be perfectly healthy and physiologically younger. By the same logic, the race-specific reference ranges that we have proposed22 have been criticized in that many feel that it is inappropriate to raise the ‘normal’ above 4.0 ng/ml in a high-risk group regardless of age. Specifically, Littrup feels that our values are perhaps too complex and would favor only two PSA ‘normals’ >2.0 ng/ml for ‘high-risk men’ and >4.0 ng/ml for

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Table 1.1. Comparison of Walter Reed/Center for Prostate Disease Research PSA reference ranges for maximal prostate cancer detection vs. traditional age-adjusted and original normal PSA values.

WR/CPDR ASRRs for maximum detection22 (ng/ml) Age (years)

African American

40−49 50−59 60−69 70−79

0−2.0 0−4.0 0−4.5 0−5.5

Caucasian

Traditional PSA ‘normal’ for all men (ng/ml)

Traditional ASRRs based on Causcasian men Mayo Clinic21 (ng/ml)

0−2.5 0−3.5 0−3.5 0−3.5

0−4.0 0−4.0 0−4.0 0−4.0

0−2.5 0−3.5 0−4.5 0−6.5

WR/CPDR, Walter Reed/Center for Prostatic Disease Research; ASRR, age-specific PSA reference ranges.

the ‘general’ population.61 Furthermore, Powell et al. have similarly criticized our screening guidelines regarding the raising of the PSA screening threshold above that for Caucasian men.62 They reason that, for any given PSA level, the prognosis for African American men is likely worse than Caucasian men and by raising the screening threshold, we will likely lower prognosis in this high-risk group. The key point is that our traditional age-specific PSA reference ranges (ASRRs) and reference ranges for maximal cancer detection provide compelling data that a PSA of 4.0 ng/ml is too high for many patients.

A PSA OF 4.0 NG/ML IS TOO HIGH ESPECIALLY IN YOUNG MEN Despite the continuing controversy about the ‘exact’ proper PSA by age and race, the most important concept in my opinion is recognizing that a PSA of 4.0 ng/ml is too high a screening cut-point for younger men, particularly African American men between 40 and 49 years of age. Bullock et al. screened 214 Black men between 40 and 49 years of age and found a prevalence of prostate cancer of 0.9% (2 of 214) when a PSA of 4.0 ng/ml was used.63 Interestingly, this prevalence increased to 5.6% (2 of 36) when the Black men also had a family history of prostate cancer. Conversely, Catalona et al. from the same university, found that the cancer detection rate was 38% in a small group of 16 Black men who had biopsy for PSA values between 2.6 and 4.0 ng/ml.64 In a follow-up series, this same group found an even higher prevalence of 42% for African American men with a PSA between 2.6 and 4.0 ng/ml.65 Until further data are available, I believe that African American men with a PSA >2.0 ng/ml between 40 and 49 years of age should have further evaluation. In older Black men, particularly those who are healthy and in their 50s and 60s, a clinician may use our age-adjusted sensitivity-based ranges22 or may opt to be even more aggressive and use the 2.0 ng/ml advocated by Littrup61,66 or the 2.5 ng/ml recommended by Catalona and associates.64,65

LOWERED PSA REFERENCE RANGES FOR CURABLE CANCER The concept of developing PSA reference ranges not just for cancer but curable cancer is emerging. Reissigl et al. from Austria were the first group, to my knowledge, to define PSA cut-points by decade of age for curable prostate cancer.67 These PSA values ranged from 1.25 ng/ml for men in their 40s to 3.25 ng/ml for men in their 70s. Curability definitions are somewhat arbitrary unless one waits the required 10 years or more to know exactly which patients were, in fact, cured. Instead, pathologic stage and grade of radical prostatectomy patients is a reasonable surrogate of curability. To this end, Carter et al. in a large study from Johns Hopkins, defined ‘curability’ in their series as organ confined with any grade of cancer or specimen confined (negative margins, seminal vesicles, and lymph nodes) with a Gleason sum less than or equal to 6.68 I used this definition to show that only 45% of early PSA-Era Black men who underwent a radical prostatectomy at our hospital were ‘curable’.69 This compared to 74% for the predominantly White patients reported by Carter et al.68 Furthermore, by lowering the pretreatment PSA value, the curability for both Black men and White men is strikingly better. Specifically, at Johns Hopkins 94% of men with a PSA value ⭐4.0 ng/ml were curable and 83% of Black men from Walter Reed with this low PSA were curable.25 With this in mind, I have reported PSA reference ranges for curable prostate cancer in African American men who were considered cured and who had a pretreatment PSA value.70 Age-adjusted 5th, 10th and 25th percentile of pretreatment PSA was calculated to define cut-points for screening PSA values to optimize curable prostate cancer in African American men (Table 1.2). In other words, based on this preliminary study, one would biopsy Black men with a PSA value greater than approximately 1.0 ng/ml to have a 95% probability of diagnosing curable prostate cancer. Recognizing that lowering the PSA ‘normal’ is always a tradeoff of sensitivity versus specificity (unnecessary biopsies), the 90th or 75th percentile may be

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Table 1.2. Age-adjusted PSA upper limits of normal to diagnose curable prostate cancer in African American men.

5th percentile (95% sens.) 10th percentile (90% sens.) 25th percentile (75% sens.)

40–59

60–79

0.9 1.7 3.2

1.0 2.7 5.1

a better compromise. Recognize that three of four of these values are less than the traditional normal of 4.0 ng/ml. Conversely, Carter et al. have most recently further examined the concept of PSA values and curable cancer.71 Unlike our concept of lowering the PSA, they feel that age is a more important determinant of curability and that the PSA threshold should remain at 4.0 ng/ml in younger men. They contend that simply by screening younger men, we will pick up a high proportion of curable disease.

WHAT IS THE ‘NORMAL’ PSA IN YOUNG MEN? Our Department of Defense-funded CPDR has recently conducted studies showing that a PSA of 4.0 ng/ml is significantly higher than normal for young men. In 750 Black and 750 White military members between the age of 15 and 45 who had serum banked in the Army and Navy Serum Repository (ANSR), the mean PSA values were 0.52 and 0.47 ng/ml, respectively.72 The 95th percentile ranged from 1.16 to 1.38 ng/ml for the Blacks stratified by decade of age (1.38 ng/ml in the 40–49 group); for the Whites, the corresponding values were 0.71–1.13 ng/ml. Based on these data, even using a PSA value of 2.0 ng/ml as a cut-point for both Black and White men is considerably higher than these 95th percentile values. Our second study was a prospective screening study of healthy officers enrolled in the US Army War College at Carlisle Barracks, PA, USA and is a collaboration between CPDR and the Armed Forces Physical Fitness Institute. Starting in 1997, approximately 225 matriculating officers entering the school have been offered PSA testing as part of a comprehensive executive health screen. Three years of data are available for this interim analysis on 602 men between 40 and 49 years of age.73 Only 10 of 602 (1.7%) had PSA ⭓2.5 ng/ml and only 3 (0.5%) had PSA ⭓4.0 ng /ml. One of 602 (0.17%) was diagnosed with prostate cancer (PSA of 15.5 ng/ml) and had pT3 disease at radical prostatectomy. This study was conducted in very healthy, primarily Caucasian, men and our conclusions to date suggest that screening below 50 in normalrisk individuals may not be needed. However, using a PSA screening normal cut-point of ⭓2.5 ng/ml, less than 2% of men required further evaluation. Furthermore, baseline PSA data were obtained to compare with future screens, which likely will be of clinical value. A similar study is being initiated in African American military members to determine if the yield of screening would be higher.

Aside from PSA-reference ranges, Presti et al. have proposed lowering the cut-off for PSA density to 0.1 to optimize prostate cancer detection in African American men.74 Even though it has recently been proposed that less than annual PSA screening may be appropriate for younger Caucasian men who start with a PSA <2.0 ng/nl,75 PSA velocity data for black males are not fully established and, therefore, yearly testing remains prudent for this high-risk group. In summary, despite the fact that we do not yet know the exact cause or causes for the observed differences in prostate cancer in Black men, we believe that screening is justified now to lessen the disparity. Starting testing at age 40 is reasonable in an attempt to catch tumors earlier when they are smaller. Using age- and race-adjusted PSA, particularly in the men between 40 and 49 in which the cut-off is 2.0 ng/ml, should also enhance the earlier detection at a curable stage. Continued public awareness in the African American community is also needed – even a perfect screening test will not be effective if it is not recommended and no one gets it! Finally, these recommendations need confirmation by prospective clinical trials, and we should encourage the development of such trials and participation by our Black patients.

LATEST GOOD NEWS FOR AFRICAN AMERICAN MEN Through our CPDR program, we have been keeping close tabs on racial differences in prostate cancer in our equal access US Military health care system. In the fall of 2001, we published exciting data showing remarkable improvements in pathologic stage in African American men undergoing radical prostatectomy.76 Specifically, in 195 African American and 587 Caucasian men undergoing surgery between 1998 and 1999 at one tertiary center, the rate of extraprostatic extension (pT3 disease) declined from 100% to 34.8% (P = 0.007) in the Blacks and from 56.9% to 43.2% in the Whites (P = 0.269). Similarly, for positive surgical margins, the rate went from 100% to 26.1% in Blacks (P < 0.001) and from 41.2% to 27.0% for whites (P = 0.021). We believe this improvement represents equal availability of screening and better PSA testing practices for men of both races by military physicians. As noted previously, the literature supports that this improved pathologic stage end-point will eventually translate into improved disease-specific survival for these traditionally high-risk men.

CONCLUSIONS Although randomized clinical trails have yet definitively to prove or disprove the efficacy of prostate cancer populationbased screening, emerging data in the PSA-Era arguably support PSA testing in the early diagnosis of prostate cancer. Specifically, with public awareness of the disease and widespread PSA testing, smaller cancers are being detected in younger men and 5-year cancer-specific survivals are on the

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rise. Even though this lead-time effect may not translate into a long-term improvement, these changes are a necessary prerequisite to effective screening and are very promising. For high-risk African American men, a strategy consisting of an annual PSA blood test and DRE for men ⭓40 years old appears prudent. Use of age- and race-specific references ranges for PSA based on sensitivity, or maximal cancer detection, is my favored approach in this high-risk group. Specifically, for African American men between 40 and 49 years, those with a PSA value greater than 2.0 ng/ml should consider further evaluation. For older Black men (⭓50) entering screening, consideration should be given to further evaluation of men with a PSA greater than 4.0 ng/ml recognizing that any threshold chosen will be a balance between sensitivity and specificity.

14. 15. 16. 17.

18. 19.

ACKNOWLEDGMENTS

20.

The author is supported by a grant from the Center for Prostate Disease Research, a program of the Henry M. Jackson Foundation for the Advancement of Military Medicine (Rockville, MD) funded by the US Army Medical Research and Material Command.

21.

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23.

1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics 2001. CA Cancer J. Clin. 2001; 51:15–37. 2. Walsh PC. Using prostate-specific antigen to diagnose prostate cancer: sailing in uncharted waters. Ann. Intern. Med. 1993; 119:948–9. 3. Woolf SH. Screening prostate cancer with prostate-specific antigen. An examination of the evidence. N. Engl J Med. 1995; 333:1401–1405. 4. Mettlin C, Jones G, Avetett H et al. Defining and updating the American Cancer society guidelines for the cancer-related check-up: prostate and endometrial cancers. Cancer. J. Clin. 1993; 43:42–6. 5. American Urological Association: Early detection of prostate and cancer use of transrectal ultrasound. In AUA (ed.) American Urological Association 1992 Policy Statement Book, pp. 4–20. Baltimore, MD: American Urological Association, 1992. 6. US Preventive Service Task Force. Screening for prostate cancer. In Guide to Clinical Preventive Services, 2nd ed., p. 119. Baltimore, MD: Williams and Wilkins, 1996. 7. American College of Physicians. Screening for prostate cancer. Ann. Intern. Med. 1997; 126:480–4. 8. Catalona WJ, Smith DS Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostatespecific antigen-based screening. JAMA 1993; 270:948–54. 9. Catalona WJ. Screening for prostate cancer (Letter). N. Engl. J. Med. 1996; 334:666–7. 10. Morrison AS. The effects of early treatment, lead time, and length time bias the mortality experienced by cases detected by screening. Int. J. Epidemiol. 1982; 11:261. 11. Jacobson SJ, Katusic SK, Bergstralh EJ et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate specific-antigen. JAMA 1995; 274:1455. 12. Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) Program. Monogr. Urol. 1998; 19:3–19. 13. Farkas A, Schneider D, Perotti M et al. National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for

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