Prostate cancer in African American men

Prostate Cancer and Prostatic Diseases (1998) 1, 109±118 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 Review Prostate cancer in Afr...
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Prostate Cancer and Prostatic Diseases (1998) 1, 109±118 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00

Review

Prostate cancer in African American men JW Moul

Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA

Keywords: prostate; cancer; black race

Knowledge and attitudes

and lower socioeconomic groups of African Americans. Among middle socioeconomic participants there was a willingness to undergo screening and individuals possessed reasonable knowledge, however, among the low socioeconomic groups, there were many misconceptions and myths about the etiology and mortality of cancer. Fewer of the low socioeconomic men knew that prostate cancer was a greater problem in blacks than whites and many were unaware of rectal examination or blood tests. There was concern in the low socioeconomic men that blacks are `used as guinea pigs' in reference to the Tuskegee syphilis trials. There was also fear of hearing bad news and misconceptions of surgery causing cancer to spread and rectal examination having homosexual implications.6 The authors felt that culturally relevant education and establishing a patient-provider relationship of trust and respect were needed. In this light, the recently reported Detroit Education and Early Detection (DEED) study of Powell and associates must be detailed.8 The DEED program conducted prostate cancer education and screening in the Detroit area focusing on African American churches and screened 1105 black men between 1993 and 1995.8 Eighty-®ve of the 1105 men (8%) had a prostate speci®c antigen (PSA) value of greater than 4.0 ng/ml and 36 cancers (3.2% overall, 42% of men with elevated PSA) were detected. Although a success, the program was only able to reach the middle income (median $30 943) and educated (average of `some college'). The lost to follow-up rate (11.7%) and biopsy refusal rate (4.7%) in DEED was felt to be not signi®cantly higher than screening programs in white populations. In the screened DEED men who underwent radical prostatectomy, the rate of organ-con®ned disease was 65% which is higher than historic controls of black surgical patients.8,9 Considering the relatively high detection rate in this young (mean age 54.9 y) group of black middle socioeconomic men, further efforts to reach the low socioeconomic and even younger men seem most warranted.10,11

Conventional wisdom has been that African American men are more reluctant to undergo prostate cancer screening than other groups, however, a recent study has shed more light on this issue. Robinson, et al,6,7 conducted focus groups on prostate cancer screening in middle

Screening for prostate cancer in African American men

Received 22 September 1997; revised 14 Novenber 1997; accepted 19 November 1997

Early detection for prostate cancer has been practiced for many years in the form of digital rectal examination

Introduction The age-adjusted incidence of prostate cancer in African American (black) males, is 50% higher than in Caucasian (white) men and African American (black) men have the highest incidence of prostate cancer in the world.1 Differences in the probability of being diagnosed (9.6 vs 5.2%), lifetime-speci®c mortality (3 vs 1.4%), and 5 y survival rates (65 vs 78%) between blacks and whites are all indicative of a major public health problem in this population.2 The etiology for these racial differences in prostate cancer clinical behavior is unknown; hormonal, nutritional, genetic, behavioral and socioeconomic status (SES) factors have all been implicated.2 Now, in the late 1990s, as more research funding is ®nally being devoted to prostate cancer it is critically important to ®nd the cause, or causes, of this racial disparity.

The concept of race and prostate cancer The concept of race is considered a social de®nition taking into account historical, social, and economic events and is not a biological classi®cation.3 Some have argued to abandon race in variable analysis because it has no biologic meaning and is medicalization of racism.4,5 However, the fact remains that African±American or black men have a greater risk of being diagnosed with prostate cancer that is potentially more aggressive. The simple goal of our research in this area is to improve outcomes for these men. Realizing that race may be an indicator of economic status, cultural preferences or misunderstandings, and genetic succeptability for cancer behavior and development, the pragmatic mission is to understand these contributing factors to prostate cancer in this high risk group.

Prostate cancer in African American men JW Moul

110

(DRE). However, over the last ®ve years with the advent of PSA, the topic of prostate cancer screening has become a hotly contested issue.12,13 Early detection may take the form of population-based screening or case®nding.

Pros and cons of population-based screening The American Cancer Society, American Urological Association, and American College of Radiology have all come out in favor of screening for the early detection of prostate cancer.14,15 These groups recommend a DRE and PSA test for men starting at age 50 y. Notably, however, other organizations have argued against screening including the U.S. Preventive Services Task Force, the American Academy of Family Physicians and the American College of Physicians.16,17 Several factors favor the use of screening for the early detection of prostate cancer. Firstly, because patients do not experience symptoms during the early stages, they are unlikely to seek care until the disease has progressed. Secondly, improvements in detection methods have increased the prospects for identifying the disease in its early stages, when the cancer is still con®ned to the organ and is more easily treatable and often curable. Thirdly, early detection might mean the difference between life and death, as no cure has been found for advanced disease. To be of value, screening must lead to treatment that has a favorable impact on prognosis. Catalona et al,18 examined this issue by comparing disease stages in primarily Caucasian patients with prostate cancer who had or had not undergone PSA screening. 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. Similarly, in the DEED program Powell et al,8 have found that screened African Americans men had a higher likelihood of organ-con®ned, nonadvanced prostate cancer. 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 scienti®c evidence that screening will reduce disease-speci®c mortality. Indeed, many men with prostate cancer do not die from the disease, whereas many other patients die from the disease despite our best treatment 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 y of age so as to reduce the detection of such `incidental cancers' that are unlikely to affect life expectancy. These arguments against screening can be made for all men, even higher risk African American men, because we simply do not have studies proving the value of screening for prostate in any group of men at this time.

Aside from the `true' screening, or population-based screening controversy, case ®nding for prostate cancer using PSA and DRE is less debated. In other words, case ®nding 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.19 Some argue that African American men and men with a family history are high risk group individuals and prostate cancer testing in these groups represents case ®nding and not true screening. This certainly is my personal bias considering the disparity in PSA, stage, and outcomes that currently exists. Recognizing that population screening for prostate cancer using PSA and DRE have neither been proven or disproven to be effective to reduce the morbidity and mortality of the disease, authorities now recommend that physicians and health-care organizations provide the pros and cons as outlined above and let the well-informed patient decide.12 Just as it would be wrong to mandate screening, it would be just as wrong not to offer the option of early detection tests for prostate cancer, especially for high risk African American men. Despite the racial disparity in outcomes noted in the introduction, encouraging recent data from the Radiation Therapy Oncology Group (RTOG),20 US Military,21 and Veterans Administration,22 suggest that if black men are afforded the same access and care, the outcomes disparity may be minimized or eliminated. Armed with this information, we may be able to affect this disease in this population with increased public awareness, early detection programs and proper detection tools.

PSA in black men In 1992, Vjayakumar et al23 were the ®rst to report that black American men with newly diagnosed prostate cancer referred for radiotherapy had higher PSA levels than their white counterparts. A number of other preliminary reports also suggested that blacks had higher PSA.24,25 These early reports lacked proper multivariate adjustment for stage, grade, age and socioeconomic status. In 1995, our group reported on 541 consecutive men with newly diagnosed prostate cancer and showed that even with adjustment for tumor grade, age, and

Table 1 Tumor volume (TVOL) and prostate weight (pwt) for black and white radical prostatectomy prostate cancer patients by clinical stage of diseasea Black

White

Stage, grade and age

N

Tvolb

PWtc

N

Tvolb

PWtc

Total Stage T1a, T1c T2a T2b T2c, T3w

28 11 3 10 4

5.42 4.11 1.86 9.86 5.80

42.4 40.7 40.3 42.6 47.9

63 32 10 18 3

2.10 1.60 1.12 4.31 4.28

39.6 41.0 34.7 39.9 42.0

a b c

From Reference 26 Tumor volume (cc) geometric mean Prostate weight (gm) geometric mean

Prostate cancer in African American men JW Moul

clinical stage, black men had higher PSA.26 In this same study, we took a subsequent consecutive cohort of 91 black and white men who underwent a radical prostatectomy and had whole-mount processing of their prostate by careful tumor volume assessment.26 What we found startled us; even in our military equal-access health care system, the black men had much higher tumor volumes overall and within each clinical stage (Table 1). This within-stage tumor volume disparity was primarily responsible for the racial difference in PSA and PSA was a surrogate for bigger tumors in black men. Since this report most27±30 but not all31 investigators have con®rmed that black American males in general have higher PSA values than white males. Recent work from Vijayakumar and colleagues27 suggest that the racial disparity in PSA is primarily due to socioeconomics. They found no racial differences in PSA in multivariate analysis of black and white patients who had similar insurance, however, for Medicare-only patients, blacks had signi®cantly higher PSA. They concluded that blacks had higher PSA due to lack of access and/or lack of health-seeking behavior. This is not inconsistent with our results; even though our study noted above26 was performed in the equal access military, blacks may not have availed themselves to early detection opportunities and delay in diagnosis may have been responsible for the disparity. Alternatively, since the blacks in our study were, on average, 3 y younger than the whites, we and others have not ruled out potential biologic difference that caused the tumors to grow larger more quickly.

Proper use of PSA in African American men Despite the widespread use of PSA, up until recently no data existed to document the value of PSA testing and `®ne tune' the test for the early and accurate diagnosis of prostate cancer in this population. There was an urgent need to examine the proper PSA `normals' for black men and over the last year a number of groups have examined the clinical utility of PSA in this population. Smith and associates studied 861 black men for PSA and digital rectal examination (DRE) use in screening for prostate cancer.32 A PSA > 4 ng/ml had a sensitivity of 80%, speci®city of 39% and positive predictive value of 46% for cancer detection in black men. This compares to 76, 54 and 34%, respectively for white men. The DRE had corresponding values of 44, 56 and 40%, respectively for African American patients. Smith et al,32 feel that these percentages were suboptimal in this high-risk group and recommended a lower cutoff of PSA rather than the traditional 4.0 ng/ml. 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 in this high risk group of men.33 In this study, between January 1991 and May 1995 serum PSA concentration was determined for 3475 men without clinical evidence of prostate cancer (1802 Caucasian, 1673 African American) and 1783 men with the disease (1372 Caucasian, 411 African American). All PSA examinations were per-

formed using Abbott IMx assay (normal 0±4 ng/ml) in a central, single laboratory. 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 ˆ 0.40, P ˆ 0.001 for blacks and r ˆ 0.34, P ˆ 0.0001 for whites. African American men had signi®cantly higher serum PSA concentrations than Caucasian men (P ˆ 0.0001) (Figure 1). When sensitivity was plotted against 1-speci®city, 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 is 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-speci®c reference ranges by the identical methodology of Oesterling and colleagues used in their 1993 study of primarily Caucasian patients from Olmstead County, Minnesota,34 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 y, 0±6.5 ng/ml for men aged 50±59 y, 0±11.3 ng/ml for men aged 60±69 y, and 0±12.5 ng/ml for men aged 70± 79 y. 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 cancers (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 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 to

Figure 1 Distribution of PSA values for African American (AA) and Caucasian (C) by age in decades for 3475 men without clinical evidence of prostate cancer (1802 C and 1673 AA). The line represents the 5th through 95th percentiles with the heavy horizontal bar being the 95th percentile. The boxes represent the 25th to 75th percentile and the mean is a line within the box. Note that AA men have more variability in PSA which markedly increases the 95th percentiles compared to the C men. (Modi®ed from Reference 33.)

111

Prostate cancer in African American men JW Moul

112

Table 2 Walter Reed Center for Prostate Disease Research (CPDR) age-adjusted reference ranges of PSA for maximal cancer detection in African American patientsa

Table 4 Comparison of curable prostate cancer by pre-treatment PSA value in black versus predominantly white radical prostatectomy patients from two institutions

African American Decade

PSA (ng/ml)

Speci®city

0±2.0 0±4.0 0±4.5 0±5.5

93% 88% 81% 78%

40±49 50±59 60±69 70±79 a

Number Racial group Era Stage selection

From Reference 33.

Johns Hopkinsa

Walter Reed

389 Predominantly white 1989±1994 Clinically organ con®ned nonpalpable

118 All black

Curabilityb by pre-treatment PSA

maximize cancer detection. In other words, we developed reference ranges by decade in the men with prostate cancer by using the 5th percentile of PSA values. Only the lowest 5% of pre-diagnosis PSA values in the black men with cancer are `normal' and the remainder (95%) are above the normal (95% sensitivity). We refer to these range as the Walter Reed Center for Prostate Disease Research age-speci®c reference ranges for maximal cancer detection (Table 2). They maximize sensitivity (cancer detection) without undue loss of speci®city (false positive/unnecessary TRUS/biopsy). These values for maximal cancer detection for black and white men are compared to the traditional normal (0±4 ng/ml) and the previously developed age-speci®c reference ranges in Table 3. Our age and race adjusted PSA reference ranges have been met with some criticism. Littrup35 has been concerned that the average reader will not realize that our reference ranges are based on men with prostate cancer and are designed for sensitivity of cancer detection, not speci®city. He feels that we should refer to the ranges as `age-sensitive reference ranges'. Furthermore, he 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 the `general' population.36 He is also concerned that any of these presently derived decision points for PSA only address `cancer' or `no cancer' not de®ning a lower decision level for PSA in this high risk group to reduce their disproportionate mortality. While we have some concerns about Littrup's37 concepts, we do agree that PSA `normals' should attempt to detect curable prostate

Value < 4.0 ng/ml > 4.0  5.0 > 5.0 Overall

34/36 (94%) 32/36 (89%) 221/317 (70%)c 287/389 (74%)

Walter Reed Center for Prostate Disease Research age-adjusted PSA reference ranges for maximum cancer detection33

40±49 50±59 60±69 70±79

African American 0±2.0 0±4.0 0±4.5 0±5.5

Caucasian 0±2.5 0±3.5 0±3.5 0±3.5

10/12 (83%) 0/2 (0%) 43/104 (41%)c 53/118 (45%)

a

Carter HB et al, JAMA 1997; 277: 1457. Curability de®ned as organ-con®ned with any grade or capsular penetration only (no margin, seminal vesicle or node positivity) with Gleason sum of < 7. c P-value ˆ < 0.001. b

cancer, especially in this group with a historical outcomes disparity. With this in mind, our group is attempting to develop PSA reference ranges for `curable' prostate cancer in African-American men.38 Using the criteria of curability after radical prostatectomy de®ned by Carter et al,39 from Johns Hopkins, only 45% of contemporary-era black men who underwent a radical prostatectomy at our hospital were `curable.'38 This compares to 74% for the predominantly white patients reported by Carter et al.39 Furthermore, by pre-treatment PSA, Table 4 shows the striking racial differences in curability. Based on this, we are currently conducting a multicenter study to de®ne ageadjusted PSA reference ranges for curable prostate cancer using age, pre-treatment PSA value and only those men who meet the curable criteria. Despite the continuing controversy about the `exact' proper PSA by age and race, the most important concept, in our opinion, is recognizing that a PSA of 4.0 ng/ml is probably too high for younger men, such as African American men between 40±49 y of age. Bullock, et al40 screened 214 black men between 40±49 y of age and found a prevalence of prostate cancer of 0.9% (2 out of

Table 3 Comparison of Walter Reed Center for Prostate Disease Research PSA reference ranges for maximal prostate cancer detection versus traditional ageadjusted and original normal PSA value

Age

1988±1996 Clinically organ con®ned nonpalpable and palpable

Traditional PSA `normal' for all men

Traditional ageadjusted reference ranges based on Caucasian men Mayo clinic34

0±4.0 0±4.0 0±4.0 0±4.0

0±2.5 0±3.5 0±4.5 0±6.5

Prostate cancer in African American men JW Moul

214) when a PSA of 4.0 ng/ml was used. Interestingly, this prevalence increased to 5.6% (2 out of 36) when the black men also had a family history of prostate cancer. Conversely, Catalona et al,41 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±4.0 ng/ml. In a follow-up larger series, this same group found an even higher prevalence of 42% for African American men with PSA between 2.6±4.0 ng/ ml.42 Until further data are available, we believe that African American men with a PSA > 2.0 ng/ml who are between 40±49 y of age should have further evaluation.33 In older men, particularly those who are healthy and in their 50s and 60s, a clinician may use our age-adjusted sensitivity-based ranges ( > 4.0, > 4.5),33 or may opt to be even more aggressive and use the 2.0 ng/ml advocated by Littrup36 or the 2.5 ng/ml recommended by Catalona et al41 and Smith et al.42

Clinically localized prostate cancer in African American men There is an ongoing debate as to whether African American race itself is a prognostic factor for worse outcomes in localized (and advanced) prostate cancer. As noted above, data from the Radiation Therapy Oncology Group (RTOG),20 US military,21 and Veterans Administration,22 suggest that race alone is not a prognostic factor. In particular, the study by Optenberg and associate deserves further comment.21 They studied 1606 patients (7.5% black) who were treated in the US Military health care system between 1973 and 1994. They found that blacks entered active treatment and exhibited a higher relative risk of cancer in younger age groups, presented with higher stage, and demonstrated increased progression to distant metastatic disease. In multivariate analysis with stage, grade, and age, race was not an independent prognostic factor. In fact, for men with metastatic disease there was a clear trend for blacks to have greater survival. Despite the fact that race itself did not remain as a prognostic factor, what was responsible for blacks presenting at a younger age with more advanced disease? Along similar lines, a

recent SEER database study in metropolitan Detroit found that blacks had a poorer survival than whites in all stages of disease that was especially evident in younger men ( < 65).43 Powell et al,44 also found that survival was worse for African American men under age 65 y but better for men over age 65 y and used the phrase, `ethnic survival crossover'. More study needs to be done to determine if younger black men do have a worse survival and, if so, the cause of this disparity.

Radical prostatectomy in African American men Our group and others have been studying men who have undergone radical prostatectomy and comparing outcomes and tumor characteristics by race to gain insight. In Table 5 we have summarized a number of series of radical prostatectomy comparisons in black and white men. Moul et al,43 and Powell et al,44 found that blacks had signi®cantly higher pretreatment PSA and positive surgical margins. Conversely, Ibrahim et al,46 and Fowler et al,22 in smaller experiences, found no signi®cant differences in organ-con®ned or marginpositive rates by race. In a careful study of 102 whole-mounted radical prostatectomies, 32 (31.4%) of whom were black, Moul et al,47 found that blacks had higher tumor volumes in all clinical stage categories. Overall, the black men had a mean tumor volume of 4.98 cc vs 3.37 cc in the white patients. This greater tumor volume was associated with more adverse pathologic features. Capsular involvement (68.8% for blacks vs 57.1% for whites), margin positivity (58.1% vs 45.7%) and mean highest Gleason sum (6.38 vs 6.10) were all higher among black patients.47 Similarly, Pettaway et al,48 from MD Anderson Cancer Center found that 61% of African American radical prostatectomy patients had adverse pathologic features. Regarding tumor grade in radical prostatectomy specimens from black and white patients, data has been con¯icting. In our study of 107 black and 366 white surgical patients,45 the patients with Gleason sum categories of 3±4, 5±6, 7, and  8 were not signi®cantly different by race. As noted above, however, the mean

Table 5 Pathological variables of radical prostatectomy specimens in black and white patientsÐvarious series Organ con®ned N (%)

Margin positive N (%) 51 (50.5) 133 (38.4)

Race

N

Mean pre-RX PSA (ng/ml)

45

Black White

107 366

15.9 10.0

41 (39.1) 161 (46.5)

Powell et al

44

Black White

120 249

19.4 14.0

37 (31) 106 (43)

64 (58) 89 (40)

Ibrahim et al

46

Black White

78 879

N/S

42 (54) 422 (48)

25 (32) 237 (27)

Fowler et al

22

Black White

49 89

N/S

31 (63) 55 (62)

7 (14.3) 10 (11.2)

Pettaway et al

48

Black White

38 118

22 13

15 (39) N/S

N/S

Authors

Ref.

Moul et al

a

N/S ˆ Not Stated in Publication.

Positive seminal vesicle N (%) 15 (14.3) 41 (11.7) N/Sa N/S

Positive lymph nodes N (%) 0(Ð) 9 (2.6) N/S N/S

6 (12) 9 (10)

1 (2) 1 (1)

8 (21) N/S

N/S

113

Prostate cancer in African American men JW Moul

114

highest Gleason sum was higher for blacks.47 Powell et al,44 did not ®nd differences in the mean and median Gleason sum in both biopsy and radical specimens by race. Conversely, Littrup35 has found that signi®cantly greater numbers of cancer biopsy cores among African American men contain Gleason sums  7 (P < 0.001). In 1400 sextant biopsies, 70% of whom were in black men, the blacks had more cores involved (mean 3.2) compared to whites (mean 2.4) (P ˆ 0.008) even controlling for PSA level.49 Furthermore, the Gleason sum was signi®cantly higher in African±American men controlling for PSA between 2±20 ng/ml (P ˆ 0.025). These investigators also performed survival modelling and felt that the higher volumes of Gleason grade 4 component seen in African American men account for the 40±50% greater mortality seen in national statistics.50 Regarding recurrence and survival analysis of radical prostatectomy by race, results are also con¯icting. Our survival analysis for 107 black and 366 white men was very interesting and points to the need for careful multivariate analysis when trying to determine if race itself is a prognostic factor.45 Overall, the African American men had a lower recurrence-free survival. In other words, at a mean follow-up of 23.3 months, black men were more likely to have had a recurrence generally de®ned as a rising PSA as their ®rst evidence of failure. Even in one multivariate analysis with adjustment for pathologic stage, grade, and pre-treatment PSA and acid phosphatase, black race remained as an independent prognostic factor. However, in another multivariate analysis when we include margin positivity in the model, race (P ˆ 0.083) was no longer an independent prognostic factor. Because clinical stage and pathologic stage categories may not accurately re¯ect tumor volume and subtle pathologic features such as margin positivity and volume of high grade cancer, it will be imperative to include these factors in multivariate analysis when deciding if race itself affects outcomes. The Duke University group initially found that cancerspeci®c death rates were not different for black and white radical prostatectomy patients.46 However, a more recent analysis suggested that black men with specimen-con®ned and margin positive disease had more rapid PSA recurrence due to higher grade and larger volume disease.51 The cancer-speci®c death rates by pathologic stage groupings were not different by race. The Wayne State University group now has a cohort of 928 radical prostatectomy patients and in subset analysis of those operated between January 1991 to December 1993, the PSA-recurrence rate in blacks is 34.2% versus 22.4% in whites.52 To date, however, our study43 is the only one to suggest that blacks have higher PSA-recurrence in multivariate analysis and further work is needed. We are currently conducting a prospective radical prostatectomy study in which the Armed Forces Institute of Pathology and CPDR are collaborating to compare three dimensional tumor volumes and careful quantitative histology to outcomes of black and white men. Even if race itself is not found to be an independent prognostic marker when including these comprehensive pathologic assessments, what is responsible for the worse pathologic ®ndings? Considering that the black men in our studies and others are 1±3 y younger than the white men yet have

bigger and more adverse pathologic tumors, is biology or behavior and access to blame?

Clinically localized prostate cancer in African Americans treated by radiotherapy The outcomes of black patients with clinically localized prostate cancer compared to white patients treated with radiation has also been studied with con¯icting results. An early study by Levine and Wilchinsky found no signi®cant difference by race.53 Similarly, Page and Kuntz found no signi®cant difference by race in the Veterans Administration health care system and concluded that equal socioeconomic status and access to care were responsible.54 However, in other socioeconomic and access studies, Hussain et al,55 found that blacks had higher grade disease and implicated higher cigarette smoking and carcinogenic tumor dedifferentiation. Ruffer et al,56 in a Patterns of Care analysis found that blacks had been treated by a lower dose of radiation than whites and implicated this factor as at least partially responsible for poorer outcomes observed. More recently, a number of larger retrospective reviews of outcomes of radiation by race have been reported. Natarajan et al,57 in American College of Surgeons surveys from 1974 and 1978 found that prostate cancerspeci®c survival was signi®cantly less for black than white patients. Austin et al,58 found a poorer survival in black versus white radiated patients even with stage and grade adjustment. Roach et al,20 performed a retrospective analysis of three Radiation Therapy Oncology Group trials (RTOG). In two of the three (77-06, 83-07) race was not an independent prognostic factor. However, in RTOG 75-06, blacks had signi®cantly higher prostatic acid phosphatase values and the authors implicated more advanced disease in blacks and possibly that race was an independent factor. Aziz et al,59 found that black radiated patients were more likely to have Gleason sum of 7±10 which corresponded to higher stage and lower survival but multivariate analysis was not performed. Similarly, Kim et al,60 studied 489 white and 157 black irradiation patients ®nding that 40% of blacks vs 26.% of whites (P < 0.001) had poorly differentiated tumors. Blacks had signi®cantly worse overall survival and even with stage strati®cation, blacks with stage C disease had a worse cause-speci®c survival. The 5 and 10 y cause-speci®c survival was 61 and 28% for blacks and 79 and 57% for whites (P ˆ 0.0005). Unfortunately, no multivariate analysis was performed. Conversely, Lawton et al,61 reviewed 819 irradiated patients and although blacks had higher stage at presentation, there was no survival difference stage for stage by race. My own bias is that behavior and access are largely at fault. African American men have simply not been educated about prostate cancer and the need for early detection. If early detection programs were more universally available and accepted starting at age 40 y, I believe we would detect the majority of prostate cancer when they were smaller and with fewer adverse pathologic features and would lessen or eliminate the current racial survival disparity. As previously noted, this appears to be borne out in the Detroit Education and Early Detection (DEED)

Prostate cancer in African American men JW Moul

study results.8 Considering the DEED study used a PSA normal of up to 4.0 ng/ml it is tantalizing to speculate that if we use a lower PSA reference range of 2.0 or 2.5 ng/ml in men between 40±49 y as discussed earlier33,35,42 and encourage screening in these younger African American men, that we can have even a greater impact.

Advanced prostate cancer in African American men Con¯icting data has been reported for outcomes of black and white men with metastatic prostate cancer. While SEER data report a worse survival outcomes for black men stage for stage,62 recent studies have suggested a better survival for black men with metastatic disease8,21,44 or equal survival to Caucasian men.22 Fowler et al,13 have recently studied the PSA response to hormonal therapy in black and white men and found no difference. Furthermore, the response to delayed antiandrogen treatment and antiandrogen withdrawal was similar for black and white patients. They concluded that androgen dependence and androgen independence are similar for black and white men with prostate cancer. While this may be true, basing these conclusions simply on PSA response may be naive and further research is needed.64

Are there biological differences in prostate cancer between black and white patients? Based on the preceding discussion of PSA, PSA-based screening and localized and advanced disease, this question remains to be answered. Although my own bias is that most, if not all, of the racial disparity may be explained by lack of awareness, access and delay in diagnosis, some data suggests true biologic differences. Some of the most compelling evidence for biologic difference is the work of Sakr and colleagues from Wayne State University.65,66 In landmark autopsy studies of young black and white men who died of other causes, they found that blacks harbored more high-grade prostatic introepithelial neoplasia (PIN) than age-matched whites. As previously noted, this research group is also now reporting greater volume of high grade (Gleason score  4) cancer in African American men.35,49,50 Some factor or factors, presumably biologic, is contributing to this PIN and high grade cancer disparity. Could this biologic factor be genetic, hormonal, a combination of these, or related to environmental factors such as diet? Hormonal differences between black and white men has been touted as a possible biologic factor that could explain the racial difference in prostate cancer. Ross and colleagues have found that young black males have higher testosterone and higher 5-alpha-reductase activity than age-matched Caucasian and Japanese men.67±69 Furthermore, recent study of the androgen receptor show intriguing racial differences.70±72 African American men, in general, have shorter CAG (glutamine) repeat lengths in their androgen receptor gene sequence. This shorter length reportedly renders the androgen receptor more active. Much more work is necessary to study the

androgen signaling pathway to determine if these differences contribute to prostate cancer behavior in various racial groups. Diet has long been postulated to contribute to prostate cancer behavior and play a role in observed racial differences. Early studies suggested that as blacks migrated from Africa and began consuming a Western diet high in fat and meat, this was responsible for increasing prevalence of prostate cancer.73 This was based on the assumption that the prevalence of prostate cancer in Africa was very low. New data from some of the more developed African countries suggest that the rate of prostate cancer in native African blacks is actually quite high despite a non-Western diet.74 Furthermore, recent data from Whittemore et al,75 suggests that high fat diet may only explain a minority of the racial difference in prostate cancer. Conversely, Powell76 feel that high fat diet plays a major role in explaining the racial difference in prostate cancer. They feel that a high fat diet consumed by African Americans leads to more bioactive lipids in their biologic system that contributes to prostate cancer progression.77,78 They have studied 12-lipoxygenase (12-LOX), a fatty acid metabolite, in 122 prostate cancer tissue and matched control tissue from radical prostatectomy patients.78 Although it was not statistically signi®cant, the authors did ®nd higher levels of 12-LOX in most subcategories of African Americans (T2, poorly differentiated, age 51±60 y) and used this data to support a dietary link to prostate cancer behavior by race. Reduced levels of vitamin D metabolites has also been implicated in the increased risk of prostate cancer in black men,2 however, recent study has cast doubt that vitamin D is related to prostate cancer risk.79 Much further work in these areas needs to be performed. It is intriguing to speculate that there may be racial differences in various genes that may contribute to the observed clinical disparity in prostate cancer. Aside from the recent studies of CAG repeats in the androgen receptor noted above,70±72 very little focused molecular epidemiology work has been performed. Our group has not found signi®cant racial differences in the incidence of ras,80 c-erb-B2,81 cathepsin-D,82 EGFR,82 p53,82 bcl-2,84 p16,84 and Ki-67 proliferation.86 Similarly, Sarkar et al,87 have not found racial differences in the expression of cerb-B-2. Conversely, deVere White et al88 recently reported that African Americans had a higher rate of p53 protein expression and the racial difference was most striking for diploid tumors. In a separate line of reasoning, Hayes et al,89 has studied family history of prostate cancer in black and white patients. They found equal familial prostate cancer by race and concluded that the ethnic disparity in incidence is in¯uenced by environmental and not genetic factors. Furthermore, the recent discovery of the HPC-1 (hereditary prostate cancer 1) locus on chromosome 1 in both black and white familial prostate cancer suggest that unique genetic factors may not be principally responsible for the observed racial differences.90 Finally, viral infection has been implicated as a risk factor for prostate cancer. In a preliminary study, Wideroff et al,91 were unable to show any differences in human papillomavirus (HPV) oncogenic viral DNA content in prostate cancer tissues from black and white patients. Further work with other viral DNA sequences is indi-

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cated. Aside from viral infection, the degree of in¯ammation and quanti®cation of prostatitis by race needs investigation. Not only is this important to account for PSA differences, but it is conceivable as an etiologic factor. In our whole-mount prostatectomy series, we are quantifying the volumetric amount of in¯ammation/prostatitis by race.

Conclusions The incidence of prostate cancer in African American men is higher than that of other racial groups and many studies demonstrate a higher recurrence rate and poorer survival for these men. In studies of localized prostate cancer, black men generally have higher PSA due to larger tumors. Whether the observed differences are due to environmental or biologic factors (or a combination) is open to debate. Known environmental factors that have contributed include lack of access or knowledge and/or unwillingness to seek care which causes delay in diagnosis and more advanced disease at presentation. Despite this, or in addition, the observation that a subset of blacks tend to be diagnosed at a younger age and harbor more high grade prostatic intraepithelial neoplasia and high grade cancer suggest other factors at play. Whether other environmental promoters, such as a high fat diet, are responsible or that genetic differences exist must await further study. Aside from reported genetic differences in the androgen receptor gene, other studies with sporadic and familial prostate cancer have not found signi®cantly different genetic alterations by race. Despite this continuing debate regarding causation, new efforts to educate and screen African American men have a good likelihood of helping to diagnose prostate cancer earlier so that it can be treated more effectively and lessen the currently observed disparity.

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