Urologic Oncology: Seminars and Original Investigations 33 (2015) 330.e9–330.e17
Original article
Earlier prostate-specific antigen testing in African American men—Clinical support for the recommendation Amanda F. Saltzman, M.D.a, Suhong Luo, M.P.Hb,c, Jeffery F. Scherrer, Ph.D.b,d, Kenneth D. Carson, M.D.b,c, Robert L. Grubb III, M.D.b,e, M'Liss A. Hudson, M.D.b,f,* a
b
Department of Urology, Louisiana State University Health Sciences Center, New Orleans, LA Clinical Research and Epidemiology Workgroup, John Cochran Veterans Affairs Medical Center, St. Louis, MO c Division of Oncology, Washington University School of Medicine, St. Louis, MO d Department of Family and Community Medicine, Saint Louis University, St. Louis, MO e Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO f Department of Urology, Diagnostic Clinic of Longview, Longview, TX Received 10 November 2014; received in revised form 14 February 2015; accepted 21 March 2015
Abstract Background: To determine whether prostate-specific antigen (PSA) testing in African American veterans (AAVs) aged 40 to 54 years is associated with high-risk prostate cancer characteristics compared with AAVs aged 55 to 70 years or white veterans (WVs) aged 40 to 54 years. Methods: A total of 231,174 healthy veterans aged 40 to 70 years without clinical evidence of prostate cancer underwent PSA testing between October 1, 2000, and September 30, 2007. Clinicopathologic tumor characteristics were available for 1,044/1,059 AAVs and 1,006/ 1,971 age-matched WVs diagnosed with prostate cancer after a PSA level 44 ng/ml triggered prostate biopsy. Tumor characteristics of AAVs aged 40 to 54 years were compared with AAVs 55 to 70 years, WVs 40 to 54 years, and WVs 55 to 70 years. Results: Of PSA-tested veterans aged 40 to 54 years diagnosed with prostate cancer, there were no racial differences in prebiopsy PSA levels, prostate cancer grade, or clinical stage at diagnosis. AAVs aged 40 to 54 years were more likely to have Z3 positive cores (P ¼ 0.0229) and were less likely to be active surveillance candidates (P ¼ 0.0340) compared with similarly aged WVs. AAVs aged 55 to 70 years were more likely to have high-grade (P ¼ 0.0204) and higher clinical stage (P ¼ 0.0195) prostate cancer than AAVs aged 40 to 54 years. Conclusions: This large national cohort study suggests that PSA testing at an earlier age for African American men may allow diagnosis of lower risk prostate cancer, potentially reducing disparate outcomes between AAVs and WVs. r 2015 Elsevier Inc. All rights reserved.
Keywords: Prostate-specific antigen; African American men; Prostate cancer
1. Introduction In the United States, African American (AA) men are more than twice as likely to die of prostate cancer as white men are [1]. Racial disparities in prostate cancer mortality have been associated with AA men having reduced access to prostate cancer screening services and less timely receipt of quality health care than white men are [2–5]. Racial differences in prostate tumor biology have also been Corresponding author. Tel.: þ1-504-402-7945. E-mail address: [email protected] (M.A. Hudson). *
http://dx.doi.org/10.1016/j.urolonc.2015.03.018 1078-1439/r 2015 Elsevier Inc. All rights reserved.
observed, but reported studies may be biased by socioeconomic, educational, and cultural variables [6]. When clinicopathologic features of prostate cancers at diagnosis in AA men are compared with white men in general population studies, the following racial disparities are observed: (1) higher tumor grade, (2) greater likelihood of nonlocalized, advanced-stage prostate cancer, (3) higher tumor volume in radical prostatectomy specimens, (4) higher index prostate-specific antigen (PSA) levels, and (5) less likelihood of being in a low-risk prognostic strata [7]. Limited data are available regarding prostate cancer screening outcomes in AA men and whether racial differences in
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tumor biology exist when equal insurance coverage is available [8–10]. Prostate screening guidelines identify AA men as a high-risk group and recommend PSA testing at an early age for them [11–13]. Among regular users of Veterans Health Administration (VHA) health care, 84% of healthy veterans aged 40 to 70 years undergo PSA testing, and no disparities toward AA veterans (AAV) are observed in the use of prostate cancer screening and detection tools [14]. This unique cohort has equal insurance coverage and overcomes some biases associated with community samples or patient population studies with uncertain coverage. If access to health care is equal (as in our population) and tumor biology is the same between AAVs and white veterans (WVs), then there should be no differences in tumor characteristics between these groups of men. We seek to determine whether PSA testing in AAVs aged 40 to 54 years is associated with high-risk prostate tumor characteristics when compared with AAVs aged 55 to 70 years or WVs aged 40 to 54 years. 2. Methods We previously reported a national cohort of 231,174 healthy male veterans aged 40 to 70 years without clinical
evidence of prostate cancer who underwent PSA testing between October 1, 2000 and September 30, 2007 (Fig. 1) [14]. This is a retrospective review of a database that combined prospectively collected data from a cancer registry supplemented by retrospective electronic medical record (EMR) chart review and secondary administrative data. We captured prostate cancer diagnosis using the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) [15] code 185 for any inpatient or outpatient visit following a PSA level 44.0 ng/ml and prostate biopsy procedure code 55700. We used 2 outpatient clinic stops or 1 inpatient admission associated with ICD-9 code 185 to define the presence of prostate cancer. Clinicopathologic tumor characteristics were obtained from the Veterans Administration Central Cancer Registry and from EMR reviews. The variables recorded were prebiopsy PSA level, biopsy Gleason scores and sum [16,17], clinical TNM classification of malignant tumors [18], number of total biopsy cores, and number and laterality of positive cores for prostate cancer. For analyses, we retrospectively reviewed all available EMRs for AAVs diagnosed with prostate cancer and a similar number of age-matched WVs diagnosed with prostate cancer in this cohort. The age-matched WVs with prostate cancer
Consort Diagram 3 were regular VA users, who had a PSA test Healthy AA and white veterans ages 40-70 y, who between 10/1/2000 and 09/30/2007: 231,174 PSA tested white veterans: 183,170
PSA tested AA veterans: 48,004
43,064
PSA = 0-4 ng/mL
White veterans with PSA > 4 ng/mL: 15, 754
AA veterans with PSA > 4 ng/mL: 4,940
3,193
167,416
11,278
No prostate biopsy
AA veterans with prostate biopsy aer PSA > 4 ng/mL: 1,747
White veterans with prostate biopsy aer PSA > 4 ng/mL: 1.971 No prostate cancer
691
2,505
AA veterans diagnosed with prostate cancer: 1,059
14
White veterans diagnosed with prostate cancer: 1,971 No data in VACCR/unable to locate EMR
AA veterans with recorded tumor characteriscs: 1,045
218
White veterans with recorded tumor characteriscs: 1,753
39
No EMR review
709
AA veterans with recorded tumor characteriscs and that underwent EMR review: 1,044
White veterans with recorded tumor characteriscs and that underwent EMR review: 1,006
Fig. 1. Consort diagram.
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undergoing EMR review were compared with those WVs with prostate cancer not included in the EMR review, and no differences were noted between these 2 groups with respect to prebiopsy PSA level, Gleason scores, or TNM stage classification. To standardize the data, we report the Gleason scores and sums found on prostate biopsy for all patients. The retrospective observation period ended August 31, 2012. We used a modification of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for very low-risk prostate cancer criteria [19] of PSA level o10 ng/ml, clinical stage r2a, Gleason sum r6, and fewer than 3 biopsy cores to define active surveillance candidacy. We assumed up to 20-years life expectancy for our patients, as Z95% of our patients had a Charlson-Romano score r3 [14,20]. The St. Louis VHA Institutional Review Board approved this study and waived informed consent. Bivariate associations between age and race and prebiopsy PSA level, biopsy Gleason scores and sum, clinical TNM staging classification, number of total biopsy cores, number of positive biopsy cores for prostate cancer, presence of unilateral or bilateral disease, and candidacy for active surveillance were evaluated with chi-square tests by Suhong Luo. The null hypothesis was rejected if the P value of the Wald chi-square test for the parameter estimate was o0.05. 3. Results The cohort is described in Fig. 1 and results are summarized in Tables 1 to 4. Overall, 48,004/231,174 (21%) of all PSA-tested subjects were AAVs, 32,541/ 129,034 (25%) of those aged 40 to 54 years were AAVs, and 15,463/102,140 (15%) of those aged 55 to 70 years were AAVs. 3.1. Biopsy Gleason sum (tumor grade) AAVs aged 40 to 54 years in this cohort were significantly less likely to be diagnosed with high-grade prostate cancer than AAVs aged 55 to 70 years (Table 3, P ¼ 0.0204). There was no difference in grade distributions between AAVs aged 40 to 54 years and WVs aged 40 to 54 years (Table 1, P ¼ 0.4347). There was no difference in grade distribution between WVs aged 40 to 54 years and WVs aged 55 to 70 years (Table 4, P ¼ 0.1718). Subcategorization of intermediate-grade (Gleason 7) cancers into patterns 4 þ 3 vs. 3 þ 4 showed that WVs were more likely to have 4 þ 3 disease than AAVs were, although this difference only reached significance (P o 0.0001) in veterans aged 55 to 70 years (Tables 1 and 2).
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Table 1 Comparisons of characteristics between veterans aged 40 to 54 years Characteristics
AAVs aged 40–54 years, n ¼ 397
WV ages 40–54 years, n ¼ 281
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
76.6 14.1 9.3
80.1 13.2 6.8
0.2057
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
53.2 34 16.4 17.6 11.6 1.3
56.2 33.8 12.5 21.4 10 0
0.4347
Gleason score 7, % 3þ4 4þ3
48.2 51.8
36.8 63.2
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
29.2 69.5 1.3
31.3 68.7 0
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
45.3 35 13.9 2 2.3 1.5
48.8 36.7 10.3 2.1 2.1 0
0.3396
Clinical T category T1c/T2a ZT2b Unknown
86.9 6.8 6.3
92.9 5 2.1
0.4465
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
5.3 58.2 8.1 28.5
3.6 51.6 3.9 40.9
0.4086
Number of positive cores, % 1 2 3 or more Unknown
16.1 13.6 40.6 29.2
18.9 13.2 27.8 40.2
0.0229
Active surveillance, % Candidate Not candidate Unknown
14.9 68.3 16.9
20.3 59.8 19.9
0.0340
Laterality Unilateral Bilateral Unknown
49.6 44.6 5.8
52.3 35.6 12.1
0.0935
0.0893
0.6314
3.2. Clinical TNM staging classification In our cohort, Z93% of veterans were diagnosed with clinically localized (stage I or II) disease, and no racial disparities for stage at diagnosis were observed in overall
cohort. No racial disparities in clinical TNM stage were noted when AAVs aged 40 to 54 years were compared with WVs aged 40 to 54 years (Table 1, P ¼ 0.3396). Older AAVs (55–70 y) were noted to have higher stage
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Table 2 Comparisons of characteristics between veterans aged 55 to 70 years
Table 3 Comparisons of characteristics between AAV
Characteristics
Characteristics
AAVs aged 55–70 years, n ¼ 647
WVs aged 55–70 years, n ¼ 725
P value
AAV aged 55–70 years, n ¼ 647
AAV aged 40–54 years, n ¼ 397
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
72.3 18.2 9.4
81.1 12.3 6.6
0.0005
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml
72.3 18.2
76.6 14.1
0.2908
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
46.2 37.9 19.6 18.2 15 0.9
50.8 35.6 11 24.6 13.7 0
0.1501
46.2 37.9 19.6 18.2 15 0.9
53.2 34 16.4 17.6 11.6 1.3
0.0204
Gleason score 7, % 3þ4 4þ3
Gleason score 7, % 3þ4 4þ3
51.8 48.2
31 69
48.1 51.9
51.8 48.2
0.4918
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
33.2 65.8 0.9
38.2 61.8 0
33.2 65.8 0.9
29.2 69.5 1.3
0.1870
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
37.4 39.7 15.3 3.6 2.8 1.2
43.7 37.4 14.2 2.2 2.2 0.3
0.0206
37.4 39.7 15.3 3.6 2.8 1.2
45.3 35 13.9 2 2.3 1.5
0.0195
Clinical T category T1c/T2a ZT2b Unknown
Clinical T category T1c/T2a ZT2b Unknown
88.3 6 5.7
86.5 7.5 6.1
0.2867
88.3 6 5.7
86.9 6.8 6.3
0.5998
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.2 56.1 5.4 32.3
5.3 58.2 8.1 28.5
0.1182
0.0293
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.2 56.1 5.4 32.3
6.5 42.2 2.6 48.7
Number of positive cores, % 1 2 3 or more Unknown
0.3351
16.7 16.1 33.9 33.4
16.1 13.6 40.6 29.2
0.2078
15.9 10.8 26.5 46.9
Number of positive cores, % 1 2 3 or more Unknown
16.7 16.1 33.9 33.4
Active surveillance, % Candidate Not candidate Unknown
14.9 66.1 19
0.6304
17.2 70.8 12.1
14.9 68.3 16.9
0.5479
17.2 70.8 12.1
Active surveillance, % Candidate Not candidate Unknown
Laterality Unilateral Bilateral Unknown
47 34.2 18.8
0.0368
48.8 45.3 5.9
49.6 44.6 5.8
0.8109
48.8 45.3 5.9
Laterality Unilateral Bilateral Unknown
o0.0001
0.0731
3.3. Tumor volume disease than either AAVs aged 40 to 54 years (Table 3, P ¼ 0.0195) or WVs aged 55 to 70 years (Table 2, P ¼ 0.0206).
Within the EMR reviewed cohort, most veterans underwent 6 to 12 core biopsies, and no racial disparities were
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more likely to have Z3 positive cores compared with WVs aged 40 to 54 years in our cohort (Table 1, P ¼ 0.0229).
Table 4 Comparisons of characteristics between WVs Characteristics
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WVs aged 55–70 years, n ¼ 725
WV aged 40–54 years, n ¼ 281
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
81.1 12.3 6.6
80.1 13.2 6.8
0.9226
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8
50.8 35.6 11.0 24.6 13.7
56.2 33.8 12.5 21.4 10
0.1718
Gleason score 7, % 3þ4 4þ3
31 69
36.8 63.2
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4)
38.2 61.8
31.3 68.7
0.0415
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
43.7 37.4 14.2 2.2 2.2 0.3
48.8 36.7 10.3 2.1 2.1 0
0.1485
Clinical T category T1c/T2a ZT2b Unknown
86.5 7.5 6.1
92.9 5 2.1
0.1224
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.5 42.2 2.6 48.7
3.6 51.6 3.9 40.9
0.0292
Number of positive cores, % 1 2 3 or more Unknown
15.9 10.8 26.5 46.9
18.9 13.2 27.8 40.2
0.7535
Active surveillance, % Candidate Not candidate Unknown
14.9 66.1 19
20.3 59.8 19.9
0.0280
Laterality Unilateral Bilateral Unknown
47 34.2 18.8
52.3 35.6 12.1
0.6649
3.4. Prebiopsy PSA level Prebiopsy PSA levels in AAVs aged 40 to 54 years were similar in WVs aged 40 to 54 years (Table 1, P ¼ 0.2057), and AAVs aged 40 to 54 years and AAVs aged 55 to 70 years showed similar values (Table 3, P ¼ 0.2908). Significantly higher PSA levels were only noted in AAVs aged 55 to 70 years compared with WVs aged 55 to 70 years (Table 2, P o 0.0005). 3.5. Active surveillance candidacy
0.3003
observed in overall cohort regarding number of cores obtained (P ¼ 0.1167). We used the number of positive biopsy cores and presence of unilateral/bilateral disease as surrogates for tumor volume. Among the 70.8% with data on number of positive biopsies recorded, AAV aged 40 to 54 years were
Overall, 16.3% of the cohort met modified NCCN criteria for active surveillance. WVs aged 40 to 54 years were more likely to be active surveillance candidates than were AAVs aged 40 to 54 years (Table 1, P ¼ 0.0340) or WVs aged 55 to 70 years (Table 4, P ¼ 0.0280). 4. Discussion The American Urological Association and the American Cancer Society guidelines [12,13] advocate PSA testing at an earlier age in AA men than in white men (before the age of 50 and 55 years, respectively), presumably with the hope that screening AA men at an earlier age will lead to detection of prostate cancer at a clinically localized (potentially curable) stage. Although this recommendation is intuitive, data are lacking to show that performing PSA testing in AA men at an earlier age accomplishes this goal. We present the largest reported national cohort of PSAtested AA men (48,004) with insurance coverage equal to a white comparison group. Prior work with this cohort showed no racial disparities in PSA screening and performance of prostate biopsies for PSA level 44 ng/ml [14]. We limited our cohort to those undergoing prostate biopsy within the VHA to eliminate bias associated with care received outside the VHA. Surveillance, Epidemiology, and End Results (SEER) data are confounded by lack of insurance or underinsurance, timely access to health care and quality of health care, and other biases toward minority patients [1,21,22]. We addressed a younger population with a potentially longer life expectancy than is covered by Medicare (Z65 y) data. We examined the likelihood of previously reported racial disparities with respect to clinicopathologic prostate cancer outcomes including prebiopsy PSA level, Gleason scores and sum, clinical stage at diagnosis, number of positive biopsy cores, presence of unilateral/bilateral disease, and candidacy for active surveillance in 2 age groups (Table 1–4). The most significant finding of this study is the lack of disparate racial outcomes for prostate cancers detected in veterans aged 40 to 54 years (Table 1), which is in contrast
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to the outcomes in veterans aged 55 to 70 years in our cohort (Table 2) and much of the reported literature regarding prebiopsy PSA levels, tumor grade, and clinical stage at diagnosis. Prebiopsy PSA levels were similar between AAVs and WVs aged 40 to 54 years, and the majority were o10 ng/ml. In contrast, AAVs aged 55 to 70 years were more likely to have higher PSA levels compared with WVs aged 55 to 70 years, which is commonly reported [4,7,8]. The likelihood of recurrent or metastatic prostate cancer correlates with prebiopsy PSA levels; thus, this finding of similar PSA levels in younger AAVs and WVs, before a significant difference in prebiopsy PSA exists, supports the recommendation for earlier PSA testing in AA men. We found no difference in tumor grade (Gleason sum) distribution between AAVs aged 40 to 54 years and WVs aged 40 to 54 years (Table 1, P ¼ 0.4347). AAVs aged 40 to 54 years showed a significantly lower likelihood of highgrade prostate cancer compared with AAVs aged 55 to 70 years (Table 3, P ¼ 0.0204). Gleason score has been reported as the strongest predictor of disease-free survival in men with clinically localized prostate cancer (10-year follow-up, radical prostatectomy specimens) [23]. Our study suggests that earlier PSA testing (before the age of 55 y) is associated with a lower likelihood of AAVs being diagnosed with high-grade cancer and thus supports the recommendation of earlier PSA testing for AA men. We also looked at age and racial associations with intermediate-grade (Gleason 7) cancers. A difference in tumor biology has been suggested in patients with intermediate-grade (Gleason 7) prostate cancer depending on the predominant pattern (4 or 3). Prior studies have shown that subcategorization of prostate cancer into patterns 4 þ 3 vs. 3 þ 4 is associated with differences in rates of margin positivity, biochemical recurrence rates, and prostate cancer–specific mortality rates [24–26]. An unexpected finding among veterans with intermediate-grade (Gleason 7) cancer was that WVs were more likely to have Gleason 4 þ 3 disease than AAVs were, a difference that only reached significance in the older age group (Table 2, P o 0.0001). Intuitively, one would assume that AAVs would be more likely to have Gleason 4 þ 3 disease than 3 þ 4 disease than WVs, if AAVs are more likely to have high-grade disease than WVs. However, the studies reporting disparate outcomes for pattern 4 þ 3 vs. 3 þ 4 disease are predominantly white cohorts [26]. A difference in tumor biology of Gleason pattern 4 þ 3 vs. 3 þ 4 has not been established in AA men to our knowledge. In our cohort, grouping of Gleason pattern 4 þ 3 disease with Gleason 8– 10 disease as a high-risk category (as done by Fanning et al. [27]) compared with grouping of Gleason pattern 3 þ 4 disease with Gleason 3 þ 3 or lower disease as a low-risk category showed a significant difference for WVs (Table 4, P ¼ 0.0415) but not for AAVs (Table 3, P ¼ 0.1870). The presence of predominantly pattern 3 disease in AAVs may be related to sampling error within prostates containing a
larger volume of tumor, as AA men have been shown to have up to a 38% upgrading in Gleason score on radical prostatectomy specimens compared with biopsy specimens [28]. We cannot discount the possibility of interobserver variation in the grading of prostate cancer by different pathologists nor the possibility of stage migration, which has been observed in Gleason scoring before and after the 2005 International Society of Urological Pathology modifications [16]. It is possible the more common Gleason 3 þ 4 pattern observed in younger AAVs differs from Gleason pattern 3 þ 4 in WVs in its rate and propensity to evolve into 4 þ 4 disease as opposed to becoming 4 þ 3. Another important finding within our cohort was that no racial differences in clinical stage at prostate diagnosis were found in the age group of 40 to 54 years (Table 1, P ¼ 0.3396). Prior general population studies have shown AA men to be more likely to be diagnosed with advanced-stage prostate cancer than white US men [1,21]. Table 2 shows that AAVs aged 55 to 70 years are more likely to have higher clinical stage at diagnosis than WVs aged 55 to 70 years are (P ¼ 0.0206). Stage at diagnosis strongly predicts 5-year relative survival rates [1,21] with men with localized prostate cancer having a nearly 100% 5-year relative survival rate, regardless of race. This does not hold true for men with distant disease, where AA men have only a 29% 5-year relative survival rate compared with 34% for white men [1,21]. The lack of racial differences in clinical stage at diagnosis among those veterans aged 40 to 54 years further supports the usefulness of early PSA testing in AA men. SEER data for the period 1999 to 2006, which mirrors the study period of our cohort, showed some interesting differences compared with our data (Table 5). We acknowledge that our cohort and the men described in SEER are not directly comparable. Much of the difference in survival between AA and white men with prostate cancer has been attributed to barriers that prevent receipt of timely and highquality medical care, resulting in a later stage at diagnosis and disparities in treatment [3,22]. Our data suggest that a health care system that provides insurance coverage, prostate cancer screening, and detection without racial bias mitigates the racial difference in prostate cancer stage at diagnosis observed in SEER and leads to diagnosis of clinically localized, potentially curable prostate cancer in Z93% of cases. Comparisons of AA and white men from pre- and postPSA eras complement our findings by suggesting an association between aggressive earlier PSA testing in AA men and a decrease in advanced stage at diagnosis and prostate cancer–specific mortality for AA men during the post-PSA era [29]. Our findings suggest that PSA screening in younger AA men identifies disease with not only less advanced-stage disease at diagnosis but also lower prebiopsy PSA levels and lower grade disease compared with older AA men, which may, in addition to decreasing advanced stage at diagnosis, contribute to lower prostate cancer–specific mortality. Further studies are needed to
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Table 5 Comparison of SEER data to current study [39]
Time period studied (y) Number of men studied (AA/white) % Of AA men in cohort % Of AA men diagnosed with distant disease % Of white men diagnosed with distant disease % Of AA men diagnosed with clinically localized disease % Of white men diagnosed with clinically localized disease
determine if earlier PSA testing in AA men will reduce prostate cancer mortality. AA men undergoing radical prostatectomy have been shown to have greater tumor volume than white men [30]. We looked at number of positive cores and presence of unilateral/bilateral disease as surrogates for tumor volume, as we are working with prostate biopsy specimens. A significant disparate racial outcome was noted in veterans aged 40 to 54 years. AAVs in this age group were more likely to have Z3 positive biopsy cores for prostate cancer than WVs aged 40 to 54 years are (Table 1, P ¼ 0.0229). Comparison of older AAVs with WVs showed AAVs were more likely to have bilateral disease (Table 2, P ¼ 0.0368). This only reached significance for those aged 55 to 70 years, but, although a trend was observed, not significant for those aged 40 to 54 years (Table 1, P ¼ 0.0935). This supports our view that PSA level testing leading to earlier prostate cancer detection in AA men will reduce the outcome disparities observed by potentially decreasing the likelihood of extracapsular extension and positive surgical margins associated with bilateral disease on prostate biopsies, which are risk factors for prostate cancer recurrence after treatment [31]. Some might ask whether PSA testing at an earlier age in AA men merely increases the number of AA patients diagnosed with indolent disease. Diluting the pool of AA men diagnosed with prostate cancer by including more cases of indolent cancers could potentially affect the differences noted in Gleason sums when comparing AAVs aged 40 to 54 years with AAVs aged 55 to 70 years or with WVs aged 40 to 54 years. Using modified NCCN guidelines criteria for active surveillance in men with very lowrisk prostate cancer as a surrogate definition of indolent cancer, we found that younger WVs (aged 40–54 y) were more likely than older WVs (aged 55–70 y) to be active surveillance candidates (Table 4, P ¼ 0.0280). This agerelated difference was not observed for AAVs (Table 3, P ¼ 0.5479). Thus, no evidence was found that more indolent cancer was being diagnosed in younger AAVs. AAVs aged 40 to 54 years were less likely than WVs aged 40 to 54 years in our cohort to meet active surveillance criteria (Table 1, P ¼ 0.0340) [19]. Specifically, young AAVs had Z3 positive cores as the most common reason
SEER
Current cohort
1999–2006 322,840 (43,891/278,949) 13.6 6 4 79 80
2000–2007 2,050 (1,045/1,005) 51 2.6 2.4 93.5 93.9
not to qualify for active surveillance (Table 1, P ¼ 0.0229). Although higher grade and high prebiopsy PSA levels were used to disqualify a few more young AAVs than young WVs from active surveillance candidacy, these factors were not significantly different between races in the 40- to 54-years age group. Large active surveillance trials have limited outcome data on AA men [32–34]. In addition to our findings, prior evidence showed AA men meeting active surveillance criteria who underwent surgery are more likely to have higher rates of Gleason upscoring, lower rates of organ-confined disease, greater volume of cancer, greater likelihood of multifocality and transition zone cancers, higher hazard risks of biochemical recurrence, and positive surgical margins at prostatectomy. These findings from other studies also support our position that earlier PSA testing in AA men is not detecting more indolent cancer [31–34]. Rather, earlier PSA testing in AA men appears to diagnose more AA men with prostate cancer at a potentially curable stage. Comparisons of AAVs in the younger and older age groups suggest that if PSA testing is delayed to Z55 years, prostate cancers detected will have more unfavorable characteristics including higher grade, bilateral disease, and clinical stage (Table 3). Our study has limitations. This is a retrospective review of administrative data selected for the absence of incident heart disease and oversampled for depression [35]. We acknowledge that we were unable to account for socioeconomic status, education levels, or family history of patients with prostate cancer, which are known to be associated with prostate cancer outcomes [3,6,10]. We did not account for veterans using 5α-reductase inhibitors or statins or for those receiving additional care outside the VHA. Although we have used the VHA as a model of equal care without screening biases, this is not a perfect assumption as even within this system there are issues with access to care. PSA recommendations are changing rapidly [13,36–38], and a cutoff of 4 ng/ml and screening for men between the ages of 40 and 70 years may not be reflective of today's clinical practice. Biopsy data regarding number of positive cores and total number of cores in WV were less commonly reported for WVs than for AAVs and may have influenced our results.
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We acknowledge that the large screening trial populations where o5% of men participating were AA [36,37] and the VHA cohort presented here are different. When the U.S. Preventive Services Task Force [38] issued recommendations about PSA testing based on the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and European Randomised Study of Screening for Prostate Cancer (ERSPC) study [36,37], we were concerned that AA men in general were being counseled on the risks and benefits of PSA testing based on data from a study group of largely white men of European descent with no account for differences in the prostate cancer disease process in AA men. We believe that our cohort provides new and important information to AA men regarding the pros/cons of PSA testing. In summary, comparative statistics between AAVs and WVs aged 55 to 70 years confirmed previously reported disparate outcomes between races. AAVs aged 55 to 70 years were more likely than WVs aged 55 to 70 years to have higher prebiopsy PSA levels, higher clinical stage at diagnosis, and greater likelihood of bilateral disease (Table 2). When AAVs and WVs aged 40 to 54 years were compared, these differences were mitigated. No racial differences in prebiopsy PSA levels, tumor grade, or clinical stage at diagnosis were noted for veterans aged 40 to 54 years.
5. Conclusion Data from this large national cohort of PSA-tested veterans support the clinical recommendation that PSA testing at an earlier age for AA men may allow diagnosis of lower risk prostate cancer, potentially reducing the racial disparities observed in patients with prostate cancer. References [1] Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. [2] Talcott JA, Spain P, Clark JA, et al. Hidden barriers between knowledge and behavior: the North Carolina prostate cancer screening and treatment experience. Cancer 2007;109:1599–606. [3] Shavers VL, Brown ML. Racial and ethnic disparities in the receipt of cancer treatment. J Natl Cancer Inst 2002;94:334–57. [4] Klein JB, Nguyen CT, Saffore L, Modlin C 3rd, Modlin CS Jr. Racial disparities in urologic health care. J Natl Med Assoc 2010;102:108–17. [5] Underwood W 3rd, Jackson J, Wei JT, et al. Racial treatment trends in localized/regional prostate carcinoma: 1992-1999. Cancer 2005; 103:538–45. [6] Schwartz K, Powell IJ, Underwood W 3rd, George J, Yee C, Bannerjee M. Interplay of race, socioeconomic status, and treatment on survival of patients with prostate cancer. Urology 2009;74:1296– 302. [7] Chornokur G, Dalton K, Borysova ME, Kumar NB. Disparities at presentation, diagnosis, treatment, and survival in African American men, affected by prostate cancer. Prostate 2011;71:985–97. [8] Freedland SJ, Sutter ME, Naitoh J, Dorey F, Csathy GS, Aronson WJ. Clinical characteristics in black and white men with prostate cancer in an equal access medical center. Urology 2000;55:387–90.
[9] Giri VN, Ruth K, Hughes L, et al. Racial differences in prediction of time to prostate cancer diagnosis in a prospective screening cohort of high-risk men: effect of TMPRSS2 Met160Val. BJU Int 2011;107: 466–70. [10] Polednak AP. Prostate cancer treatment in black and white men: the need to consider both stage at diagnosis and socioeconomic status. J Nat Med Assoc 1998;90:101–4. [11] Powell IJ, Banerjee M, Sakr W, et al. Should African-American men be tested for prostate carcinoma at an earlier age than white men? Cancer 1999;85:472–7. [12] Wolf AM, Wender RC, Etzioni RB, American Cancer Society Prostate Cancer Advisory Committee, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin 2010;60:70–98. [13] Greene KL, Albertsen PC, Babaian RJ, et al. Prostate specific antigen best practice statement: 2009 update. J Urol 2009;182:2232–41. [14] Hudson MA, Luo S, Chrusciel T, et al. Do racial disparities exist in the use of prostate cancer screening and detection tools in veterans? Urol Oncol 2014;32:34.e9–34.e18. [15] Centers for Disease Control and Prevention. International Classification of Diseases. Ninth Revision; Clinical Modification, http://www. cdc.gov/nchs/icd/icd9cm.htm; [accessed 23.09.14.]. [16] Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL, ISUP Grading Committee. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005;29:1228–42. [17] Gleason DF, Mellinger GT. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 1974;111:58–64. [18] International Union against Cancer. Sobin LH, Wittekind CH, TNM Classification of Malignant Tumours, 6th ed New York, NY: WileyLiss; 2002. [19] NCCN Clinical Practice Guidelines for Oncology: Prostate cancer, http://www.nccn.org/professionals/physician_gls/f_guidelines.asp; 2012 [accessed 1609.14. [20] Romano PS, Roos LL, Jollis JG. Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: differing perspectives. J Clin Epidemiol 1993;46:1075–9. [21] DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA Cancer J Clin 2013;63:151–66. [22] Smedley BD, Stith AY, Nelson AR, editors. Unequal Treatment: Confronting Racial and Ethnic Disparities In Health Care. Washington, DC: The National Academies Press; 2002. [23] Bianco FJ Jr, Wood DP Jr, Cher ML, Powell IJ, Souza JW, Pontes JE. Ten-year survival after radical prostatectomy: specimen Gleason score is the predictor in organ-confined prostate cancer. Clin Prostate Cancer 2003;1:242–7. [24] Makarov DV, Sanderson H, Partin A, Epstein J. Gleason score 7 Prostate Cancer on Needle Biopsy: Is the Prognostic Difference of Gleason Scores 43 and 34 Independent of the Number of Involved Cores? J Urol 2002;167:2440–2. [25] Amin A, Partin A, Epstein. Gleason score 7 on needle biopsy: relation of primary 3 or 4 to pathologic stage and progression after radical prostatectomy. J Urol 2011;186:1286–90. [26] Laverty HJ, Droller MJ. Do Gleason patterns 4 and 3 prostate cancer represent different disease states? J Urol 2012 Nov;188:1667–75. [27] Fanning DM, Kay E, Fan Y, Fitzpatrick JM, Watson RW. Prostate cancer grading: the effect of stratification of needle biopsy Gleason Score 4 þ 3 as high or intermediate grade. BJU Int 2010;105:631–5. [28] Vora A, Large T, Aronica J, Haynes S, Harbin A, Marchalik D, et al. Predictors of Gleason score upgrading in a large African-American population. Int Urol Nephrol 2013;45:1257–62. [29] Powell IJ, Vigneau FD, Bock CH, Ruterbusch J, Heilbrun LK. Reducing prostate cancer racial disparity: evidence for aggressive early prostate cancer PSA testing of African American men. Cancer Epidemiol Biomarkers Prev 2014;23:1505–11.
A.F. Saltzman et al. / Urologic Oncology: Seminars and Original Investigations 33 (2015) 330.e9–330.e17 [30] Sanchez-Ortiz RF, Troncoso P, Babaian RJ, Lloreta J, Johnston DA, Pettaway CA. African-American men with nonpalpable prostate cancer exhibit greater tumor volume than matched white men. Cancer 2006;107:75–82. [31] Faisal FA, Sundi D, Cooper JL, Humphreys EB, Partin AW, Han M, et al. Racial disparities in oncologic outcomes after radical prostatectomy: long-term follow-up. Urology 2014;84:1434–41. [32] Dall'Era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012;62:976–83. [33] Sundi D, Ross AE, Humphreys EB, et al. African American men with very low-risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them? J Clin Oncol 2013;31:2991–7. [34] Silberstein JL, Feibus AH, Maddox MM, Abdel-Mageed AB, Moparty K, Thomas R, et al. Active surveillance of prostate cancer in African American men. Urology 2014;84:1255–61.
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[35] Scherrer JF, Chrusciel T, Zeringue A, et al. Anxiety disorders increase risk for incident myocardial infarction in depressed and nondepressed Veterans Administration patients. Am Heart J 2010;159:772–9. [36] Andriole GL, Crawford ED, Grubb RL 3rd, PLCO Project Team, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012;104:125–32. [37] Schroder FH, Hugosson J, Roobol MJ, ERSPC Investigators, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012;366:981–90. [38] Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34. [39] SEER Cancer Statistics Review 1975-2007, Prostate Cancer, http:// seer.cancer.gov/archive/csr/1975_2007/results_merged/sect_23_pros tate.pdf; [accessed 01.02.15.].
Original article
Earlier prostate-specific antigen testing in African American men—Clinical support for the recommendation Amanda F. Saltzman, M.D.a, Suhong Luo, M.P.Hb,c, Jeffery F. Scherrer, Ph.D.b,d, Kenneth D. Carson, M.D.b,c, Robert L. Grubb III, M.D.b,e, M'Liss A. Hudson, M.D.b,f,* a
b
Department of Urology, Louisiana State University Health Sciences Center, New Orleans, LA Clinical Research and Epidemiology Workgroup, John Cochran Veterans Affairs Medical Center, St. Louis, MO c Division of Oncology, Washington University School of Medicine, St. Louis, MO d Department of Family and Community Medicine, Saint Louis University, St. Louis, MO e Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO f Department of Urology, Diagnostic Clinic of Longview, Longview, TX Received 10 November 2014; received in revised form 14 February 2015; accepted 21 March 2015
Abstract Background: To determine whether prostate-specific antigen (PSA) testing in African American veterans (AAVs) aged 40 to 54 years is associated with high-risk prostate cancer characteristics compared with AAVs aged 55 to 70 years or white veterans (WVs) aged 40 to 54 years. Methods: A total of 231,174 healthy veterans aged 40 to 70 years without clinical evidence of prostate cancer underwent PSA testing between October 1, 2000, and September 30, 2007. Clinicopathologic tumor characteristics were available for 1,044/1,059 AAVs and 1,006/ 1,971 age-matched WVs diagnosed with prostate cancer after a PSA level 44 ng/ml triggered prostate biopsy. Tumor characteristics of AAVs aged 40 to 54 years were compared with AAVs 55 to 70 years, WVs 40 to 54 years, and WVs 55 to 70 years. Results: Of PSA-tested veterans aged 40 to 54 years diagnosed with prostate cancer, there were no racial differences in prebiopsy PSA levels, prostate cancer grade, or clinical stage at diagnosis. AAVs aged 40 to 54 years were more likely to have Z3 positive cores (P ¼ 0.0229) and were less likely to be active surveillance candidates (P ¼ 0.0340) compared with similarly aged WVs. AAVs aged 55 to 70 years were more likely to have high-grade (P ¼ 0.0204) and higher clinical stage (P ¼ 0.0195) prostate cancer than AAVs aged 40 to 54 years. Conclusions: This large national cohort study suggests that PSA testing at an earlier age for African American men may allow diagnosis of lower risk prostate cancer, potentially reducing disparate outcomes between AAVs and WVs. r 2015 Elsevier Inc. All rights reserved.
Keywords: Prostate-specific antigen; African American men; Prostate cancer
1. Introduction In the United States, African American (AA) men are more than twice as likely to die of prostate cancer as white men are [1]. Racial disparities in prostate cancer mortality have been associated with AA men having reduced access to prostate cancer screening services and less timely receipt of quality health care than white men are [2–5]. Racial differences in prostate tumor biology have also been Corresponding author. Tel.: þ1-504-402-7945. E-mail address: [email protected] (M.A. Hudson). *
http://dx.doi.org/10.1016/j.urolonc.2015.03.018 1078-1439/r 2015 Elsevier Inc. All rights reserved.
observed, but reported studies may be biased by socioeconomic, educational, and cultural variables [6]. When clinicopathologic features of prostate cancers at diagnosis in AA men are compared with white men in general population studies, the following racial disparities are observed: (1) higher tumor grade, (2) greater likelihood of nonlocalized, advanced-stage prostate cancer, (3) higher tumor volume in radical prostatectomy specimens, (4) higher index prostate-specific antigen (PSA) levels, and (5) less likelihood of being in a low-risk prognostic strata [7]. Limited data are available regarding prostate cancer screening outcomes in AA men and whether racial differences in
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tumor biology exist when equal insurance coverage is available [8–10]. Prostate screening guidelines identify AA men as a high-risk group and recommend PSA testing at an early age for them [11–13]. Among regular users of Veterans Health Administration (VHA) health care, 84% of healthy veterans aged 40 to 70 years undergo PSA testing, and no disparities toward AA veterans (AAV) are observed in the use of prostate cancer screening and detection tools [14]. This unique cohort has equal insurance coverage and overcomes some biases associated with community samples or patient population studies with uncertain coverage. If access to health care is equal (as in our population) and tumor biology is the same between AAVs and white veterans (WVs), then there should be no differences in tumor characteristics between these groups of men. We seek to determine whether PSA testing in AAVs aged 40 to 54 years is associated with high-risk prostate tumor characteristics when compared with AAVs aged 55 to 70 years or WVs aged 40 to 54 years. 2. Methods We previously reported a national cohort of 231,174 healthy male veterans aged 40 to 70 years without clinical
evidence of prostate cancer who underwent PSA testing between October 1, 2000 and September 30, 2007 (Fig. 1) [14]. This is a retrospective review of a database that combined prospectively collected data from a cancer registry supplemented by retrospective electronic medical record (EMR) chart review and secondary administrative data. We captured prostate cancer diagnosis using the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) [15] code 185 for any inpatient or outpatient visit following a PSA level 44.0 ng/ml and prostate biopsy procedure code 55700. We used 2 outpatient clinic stops or 1 inpatient admission associated with ICD-9 code 185 to define the presence of prostate cancer. Clinicopathologic tumor characteristics were obtained from the Veterans Administration Central Cancer Registry and from EMR reviews. The variables recorded were prebiopsy PSA level, biopsy Gleason scores and sum [16,17], clinical TNM classification of malignant tumors [18], number of total biopsy cores, and number and laterality of positive cores for prostate cancer. For analyses, we retrospectively reviewed all available EMRs for AAVs diagnosed with prostate cancer and a similar number of age-matched WVs diagnosed with prostate cancer in this cohort. The age-matched WVs with prostate cancer
Consort Diagram 3 were regular VA users, who had a PSA test Healthy AA and white veterans ages 40-70 y, who between 10/1/2000 and 09/30/2007: 231,174 PSA tested white veterans: 183,170
PSA tested AA veterans: 48,004
43,064
PSA = 0-4 ng/mL
White veterans with PSA > 4 ng/mL: 15, 754
AA veterans with PSA > 4 ng/mL: 4,940
3,193
167,416
11,278
No prostate biopsy
AA veterans with prostate biopsy aer PSA > 4 ng/mL: 1,747
White veterans with prostate biopsy aer PSA > 4 ng/mL: 1.971 No prostate cancer
691
2,505
AA veterans diagnosed with prostate cancer: 1,059
14
White veterans diagnosed with prostate cancer: 1,971 No data in VACCR/unable to locate EMR
AA veterans with recorded tumor characteriscs: 1,045
218
White veterans with recorded tumor characteriscs: 1,753
39
No EMR review
709
AA veterans with recorded tumor characteriscs and that underwent EMR review: 1,044
White veterans with recorded tumor characteriscs and that underwent EMR review: 1,006
Fig. 1. Consort diagram.
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undergoing EMR review were compared with those WVs with prostate cancer not included in the EMR review, and no differences were noted between these 2 groups with respect to prebiopsy PSA level, Gleason scores, or TNM stage classification. To standardize the data, we report the Gleason scores and sums found on prostate biopsy for all patients. The retrospective observation period ended August 31, 2012. We used a modification of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for very low-risk prostate cancer criteria [19] of PSA level o10 ng/ml, clinical stage r2a, Gleason sum r6, and fewer than 3 biopsy cores to define active surveillance candidacy. We assumed up to 20-years life expectancy for our patients, as Z95% of our patients had a Charlson-Romano score r3 [14,20]. The St. Louis VHA Institutional Review Board approved this study and waived informed consent. Bivariate associations between age and race and prebiopsy PSA level, biopsy Gleason scores and sum, clinical TNM staging classification, number of total biopsy cores, number of positive biopsy cores for prostate cancer, presence of unilateral or bilateral disease, and candidacy for active surveillance were evaluated with chi-square tests by Suhong Luo. The null hypothesis was rejected if the P value of the Wald chi-square test for the parameter estimate was o0.05. 3. Results The cohort is described in Fig. 1 and results are summarized in Tables 1 to 4. Overall, 48,004/231,174 (21%) of all PSA-tested subjects were AAVs, 32,541/ 129,034 (25%) of those aged 40 to 54 years were AAVs, and 15,463/102,140 (15%) of those aged 55 to 70 years were AAVs. 3.1. Biopsy Gleason sum (tumor grade) AAVs aged 40 to 54 years in this cohort were significantly less likely to be diagnosed with high-grade prostate cancer than AAVs aged 55 to 70 years (Table 3, P ¼ 0.0204). There was no difference in grade distributions between AAVs aged 40 to 54 years and WVs aged 40 to 54 years (Table 1, P ¼ 0.4347). There was no difference in grade distribution between WVs aged 40 to 54 years and WVs aged 55 to 70 years (Table 4, P ¼ 0.1718). Subcategorization of intermediate-grade (Gleason 7) cancers into patterns 4 þ 3 vs. 3 þ 4 showed that WVs were more likely to have 4 þ 3 disease than AAVs were, although this difference only reached significance (P o 0.0001) in veterans aged 55 to 70 years (Tables 1 and 2).
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Table 1 Comparisons of characteristics between veterans aged 40 to 54 years Characteristics
AAVs aged 40–54 years, n ¼ 397
WV ages 40–54 years, n ¼ 281
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
76.6 14.1 9.3
80.1 13.2 6.8
0.2057
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
53.2 34 16.4 17.6 11.6 1.3
56.2 33.8 12.5 21.4 10 0
0.4347
Gleason score 7, % 3þ4 4þ3
48.2 51.8
36.8 63.2
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
29.2 69.5 1.3
31.3 68.7 0
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
45.3 35 13.9 2 2.3 1.5
48.8 36.7 10.3 2.1 2.1 0
0.3396
Clinical T category T1c/T2a ZT2b Unknown
86.9 6.8 6.3
92.9 5 2.1
0.4465
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
5.3 58.2 8.1 28.5
3.6 51.6 3.9 40.9
0.4086
Number of positive cores, % 1 2 3 or more Unknown
16.1 13.6 40.6 29.2
18.9 13.2 27.8 40.2
0.0229
Active surveillance, % Candidate Not candidate Unknown
14.9 68.3 16.9
20.3 59.8 19.9
0.0340
Laterality Unilateral Bilateral Unknown
49.6 44.6 5.8
52.3 35.6 12.1
0.0935
0.0893
0.6314
3.2. Clinical TNM staging classification In our cohort, Z93% of veterans were diagnosed with clinically localized (stage I or II) disease, and no racial disparities for stage at diagnosis were observed in overall
cohort. No racial disparities in clinical TNM stage were noted when AAVs aged 40 to 54 years were compared with WVs aged 40 to 54 years (Table 1, P ¼ 0.3396). Older AAVs (55–70 y) were noted to have higher stage
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Table 2 Comparisons of characteristics between veterans aged 55 to 70 years
Table 3 Comparisons of characteristics between AAV
Characteristics
Characteristics
AAVs aged 55–70 years, n ¼ 647
WVs aged 55–70 years, n ¼ 725
P value
AAV aged 55–70 years, n ¼ 647
AAV aged 40–54 years, n ¼ 397
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
72.3 18.2 9.4
81.1 12.3 6.6
0.0005
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml
72.3 18.2
76.6 14.1
0.2908
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8 Unknown
46.2 37.9 19.6 18.2 15 0.9
50.8 35.6 11 24.6 13.7 0
0.1501
46.2 37.9 19.6 18.2 15 0.9
53.2 34 16.4 17.6 11.6 1.3
0.0204
Gleason score 7, % 3þ4 4þ3
Gleason score 7, % 3þ4 4þ3
51.8 48.2
31 69
48.1 51.9
51.8 48.2
0.4918
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4) Unknown
33.2 65.8 0.9
38.2 61.8 0
33.2 65.8 0.9
29.2 69.5 1.3
0.1870
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
37.4 39.7 15.3 3.6 2.8 1.2
43.7 37.4 14.2 2.2 2.2 0.3
0.0206
37.4 39.7 15.3 3.6 2.8 1.2
45.3 35 13.9 2 2.3 1.5
0.0195
Clinical T category T1c/T2a ZT2b Unknown
Clinical T category T1c/T2a ZT2b Unknown
88.3 6 5.7
86.5 7.5 6.1
0.2867
88.3 6 5.7
86.9 6.8 6.3
0.5998
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.2 56.1 5.4 32.3
5.3 58.2 8.1 28.5
0.1182
0.0293
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.2 56.1 5.4 32.3
6.5 42.2 2.6 48.7
Number of positive cores, % 1 2 3 or more Unknown
0.3351
16.7 16.1 33.9 33.4
16.1 13.6 40.6 29.2
0.2078
15.9 10.8 26.5 46.9
Number of positive cores, % 1 2 3 or more Unknown
16.7 16.1 33.9 33.4
Active surveillance, % Candidate Not candidate Unknown
14.9 66.1 19
0.6304
17.2 70.8 12.1
14.9 68.3 16.9
0.5479
17.2 70.8 12.1
Active surveillance, % Candidate Not candidate Unknown
Laterality Unilateral Bilateral Unknown
47 34.2 18.8
0.0368
48.8 45.3 5.9
49.6 44.6 5.8
0.8109
48.8 45.3 5.9
Laterality Unilateral Bilateral Unknown
o0.0001
0.0731
3.3. Tumor volume disease than either AAVs aged 40 to 54 years (Table 3, P ¼ 0.0195) or WVs aged 55 to 70 years (Table 2, P ¼ 0.0206).
Within the EMR reviewed cohort, most veterans underwent 6 to 12 core biopsies, and no racial disparities were
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more likely to have Z3 positive cores compared with WVs aged 40 to 54 years in our cohort (Table 1, P ¼ 0.0229).
Table 4 Comparisons of characteristics between WVs Characteristics
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WVs aged 55–70 years, n ¼ 725
WV aged 40–54 years, n ¼ 281
P value
Prebiopsy PSA, % 4–10 ng/ml 10.1–20 ng/ml 420 ng/ml
81.1 12.3 6.6
80.1 13.2 6.8
0.9226
Biopsy Gleason sum, % Z6 7 3þ4 4þ3 Z8
50.8 35.6 11.0 24.6 13.7
56.2 33.8 12.5 21.4 10
0.1718
Gleason score 7, % 3þ4 4þ3
31 69
36.8 63.2
Gleason score risk, % High risk (8–10 or 4 þ 3) Low risk (6 or 3 þ 4)
38.2 61.8
31.3 68.7
0.0415
Clinical TNM stage, % Stage I Stage IIA Stage IIB Stage III Stage IV Unknown
43.7 37.4 14.2 2.2 2.2 0.3
48.8 36.7 10.3 2.1 2.1 0
0.1485
Clinical T category T1c/T2a ZT2b Unknown
86.5 7.5 6.1
92.9 5 2.1
0.1224
Total cores sampled o6 cores 6–12 cores 412 cores Unknown
6.5 42.2 2.6 48.7
3.6 51.6 3.9 40.9
0.0292
Number of positive cores, % 1 2 3 or more Unknown
15.9 10.8 26.5 46.9
18.9 13.2 27.8 40.2
0.7535
Active surveillance, % Candidate Not candidate Unknown
14.9 66.1 19
20.3 59.8 19.9
0.0280
Laterality Unilateral Bilateral Unknown
47 34.2 18.8
52.3 35.6 12.1
0.6649
3.4. Prebiopsy PSA level Prebiopsy PSA levels in AAVs aged 40 to 54 years were similar in WVs aged 40 to 54 years (Table 1, P ¼ 0.2057), and AAVs aged 40 to 54 years and AAVs aged 55 to 70 years showed similar values (Table 3, P ¼ 0.2908). Significantly higher PSA levels were only noted in AAVs aged 55 to 70 years compared with WVs aged 55 to 70 years (Table 2, P o 0.0005). 3.5. Active surveillance candidacy
0.3003
observed in overall cohort regarding number of cores obtained (P ¼ 0.1167). We used the number of positive biopsy cores and presence of unilateral/bilateral disease as surrogates for tumor volume. Among the 70.8% with data on number of positive biopsies recorded, AAV aged 40 to 54 years were
Overall, 16.3% of the cohort met modified NCCN criteria for active surveillance. WVs aged 40 to 54 years were more likely to be active surveillance candidates than were AAVs aged 40 to 54 years (Table 1, P ¼ 0.0340) or WVs aged 55 to 70 years (Table 4, P ¼ 0.0280). 4. Discussion The American Urological Association and the American Cancer Society guidelines [12,13] advocate PSA testing at an earlier age in AA men than in white men (before the age of 50 and 55 years, respectively), presumably with the hope that screening AA men at an earlier age will lead to detection of prostate cancer at a clinically localized (potentially curable) stage. Although this recommendation is intuitive, data are lacking to show that performing PSA testing in AA men at an earlier age accomplishes this goal. We present the largest reported national cohort of PSAtested AA men (48,004) with insurance coverage equal to a white comparison group. Prior work with this cohort showed no racial disparities in PSA screening and performance of prostate biopsies for PSA level 44 ng/ml [14]. We limited our cohort to those undergoing prostate biopsy within the VHA to eliminate bias associated with care received outside the VHA. Surveillance, Epidemiology, and End Results (SEER) data are confounded by lack of insurance or underinsurance, timely access to health care and quality of health care, and other biases toward minority patients [1,21,22]. We addressed a younger population with a potentially longer life expectancy than is covered by Medicare (Z65 y) data. We examined the likelihood of previously reported racial disparities with respect to clinicopathologic prostate cancer outcomes including prebiopsy PSA level, Gleason scores and sum, clinical stage at diagnosis, number of positive biopsy cores, presence of unilateral/bilateral disease, and candidacy for active surveillance in 2 age groups (Table 1–4). The most significant finding of this study is the lack of disparate racial outcomes for prostate cancers detected in veterans aged 40 to 54 years (Table 1), which is in contrast
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to the outcomes in veterans aged 55 to 70 years in our cohort (Table 2) and much of the reported literature regarding prebiopsy PSA levels, tumor grade, and clinical stage at diagnosis. Prebiopsy PSA levels were similar between AAVs and WVs aged 40 to 54 years, and the majority were o10 ng/ml. In contrast, AAVs aged 55 to 70 years were more likely to have higher PSA levels compared with WVs aged 55 to 70 years, which is commonly reported [4,7,8]. The likelihood of recurrent or metastatic prostate cancer correlates with prebiopsy PSA levels; thus, this finding of similar PSA levels in younger AAVs and WVs, before a significant difference in prebiopsy PSA exists, supports the recommendation for earlier PSA testing in AA men. We found no difference in tumor grade (Gleason sum) distribution between AAVs aged 40 to 54 years and WVs aged 40 to 54 years (Table 1, P ¼ 0.4347). AAVs aged 40 to 54 years showed a significantly lower likelihood of highgrade prostate cancer compared with AAVs aged 55 to 70 years (Table 3, P ¼ 0.0204). Gleason score has been reported as the strongest predictor of disease-free survival in men with clinically localized prostate cancer (10-year follow-up, radical prostatectomy specimens) [23]. Our study suggests that earlier PSA testing (before the age of 55 y) is associated with a lower likelihood of AAVs being diagnosed with high-grade cancer and thus supports the recommendation of earlier PSA testing for AA men. We also looked at age and racial associations with intermediate-grade (Gleason 7) cancers. A difference in tumor biology has been suggested in patients with intermediate-grade (Gleason 7) prostate cancer depending on the predominant pattern (4 or 3). Prior studies have shown that subcategorization of prostate cancer into patterns 4 þ 3 vs. 3 þ 4 is associated with differences in rates of margin positivity, biochemical recurrence rates, and prostate cancer–specific mortality rates [24–26]. An unexpected finding among veterans with intermediate-grade (Gleason 7) cancer was that WVs were more likely to have Gleason 4 þ 3 disease than AAVs were, a difference that only reached significance in the older age group (Table 2, P o 0.0001). Intuitively, one would assume that AAVs would be more likely to have Gleason 4 þ 3 disease than 3 þ 4 disease than WVs, if AAVs are more likely to have high-grade disease than WVs. However, the studies reporting disparate outcomes for pattern 4 þ 3 vs. 3 þ 4 disease are predominantly white cohorts [26]. A difference in tumor biology of Gleason pattern 4 þ 3 vs. 3 þ 4 has not been established in AA men to our knowledge. In our cohort, grouping of Gleason pattern 4 þ 3 disease with Gleason 8– 10 disease as a high-risk category (as done by Fanning et al. [27]) compared with grouping of Gleason pattern 3 þ 4 disease with Gleason 3 þ 3 or lower disease as a low-risk category showed a significant difference for WVs (Table 4, P ¼ 0.0415) but not for AAVs (Table 3, P ¼ 0.1870). The presence of predominantly pattern 3 disease in AAVs may be related to sampling error within prostates containing a
larger volume of tumor, as AA men have been shown to have up to a 38% upgrading in Gleason score on radical prostatectomy specimens compared with biopsy specimens [28]. We cannot discount the possibility of interobserver variation in the grading of prostate cancer by different pathologists nor the possibility of stage migration, which has been observed in Gleason scoring before and after the 2005 International Society of Urological Pathology modifications [16]. It is possible the more common Gleason 3 þ 4 pattern observed in younger AAVs differs from Gleason pattern 3 þ 4 in WVs in its rate and propensity to evolve into 4 þ 4 disease as opposed to becoming 4 þ 3. Another important finding within our cohort was that no racial differences in clinical stage at prostate diagnosis were found in the age group of 40 to 54 years (Table 1, P ¼ 0.3396). Prior general population studies have shown AA men to be more likely to be diagnosed with advanced-stage prostate cancer than white US men [1,21]. Table 2 shows that AAVs aged 55 to 70 years are more likely to have higher clinical stage at diagnosis than WVs aged 55 to 70 years are (P ¼ 0.0206). Stage at diagnosis strongly predicts 5-year relative survival rates [1,21] with men with localized prostate cancer having a nearly 100% 5-year relative survival rate, regardless of race. This does not hold true for men with distant disease, where AA men have only a 29% 5-year relative survival rate compared with 34% for white men [1,21]. The lack of racial differences in clinical stage at diagnosis among those veterans aged 40 to 54 years further supports the usefulness of early PSA testing in AA men. SEER data for the period 1999 to 2006, which mirrors the study period of our cohort, showed some interesting differences compared with our data (Table 5). We acknowledge that our cohort and the men described in SEER are not directly comparable. Much of the difference in survival between AA and white men with prostate cancer has been attributed to barriers that prevent receipt of timely and highquality medical care, resulting in a later stage at diagnosis and disparities in treatment [3,22]. Our data suggest that a health care system that provides insurance coverage, prostate cancer screening, and detection without racial bias mitigates the racial difference in prostate cancer stage at diagnosis observed in SEER and leads to diagnosis of clinically localized, potentially curable prostate cancer in Z93% of cases. Comparisons of AA and white men from pre- and postPSA eras complement our findings by suggesting an association between aggressive earlier PSA testing in AA men and a decrease in advanced stage at diagnosis and prostate cancer–specific mortality for AA men during the post-PSA era [29]. Our findings suggest that PSA screening in younger AA men identifies disease with not only less advanced-stage disease at diagnosis but also lower prebiopsy PSA levels and lower grade disease compared with older AA men, which may, in addition to decreasing advanced stage at diagnosis, contribute to lower prostate cancer–specific mortality. Further studies are needed to
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Table 5 Comparison of SEER data to current study [39]
Time period studied (y) Number of men studied (AA/white) % Of AA men in cohort % Of AA men diagnosed with distant disease % Of white men diagnosed with distant disease % Of AA men diagnosed with clinically localized disease % Of white men diagnosed with clinically localized disease
determine if earlier PSA testing in AA men will reduce prostate cancer mortality. AA men undergoing radical prostatectomy have been shown to have greater tumor volume than white men [30]. We looked at number of positive cores and presence of unilateral/bilateral disease as surrogates for tumor volume, as we are working with prostate biopsy specimens. A significant disparate racial outcome was noted in veterans aged 40 to 54 years. AAVs in this age group were more likely to have Z3 positive biopsy cores for prostate cancer than WVs aged 40 to 54 years are (Table 1, P ¼ 0.0229). Comparison of older AAVs with WVs showed AAVs were more likely to have bilateral disease (Table 2, P ¼ 0.0368). This only reached significance for those aged 55 to 70 years, but, although a trend was observed, not significant for those aged 40 to 54 years (Table 1, P ¼ 0.0935). This supports our view that PSA level testing leading to earlier prostate cancer detection in AA men will reduce the outcome disparities observed by potentially decreasing the likelihood of extracapsular extension and positive surgical margins associated with bilateral disease on prostate biopsies, which are risk factors for prostate cancer recurrence after treatment [31]. Some might ask whether PSA testing at an earlier age in AA men merely increases the number of AA patients diagnosed with indolent disease. Diluting the pool of AA men diagnosed with prostate cancer by including more cases of indolent cancers could potentially affect the differences noted in Gleason sums when comparing AAVs aged 40 to 54 years with AAVs aged 55 to 70 years or with WVs aged 40 to 54 years. Using modified NCCN guidelines criteria for active surveillance in men with very lowrisk prostate cancer as a surrogate definition of indolent cancer, we found that younger WVs (aged 40–54 y) were more likely than older WVs (aged 55–70 y) to be active surveillance candidates (Table 4, P ¼ 0.0280). This agerelated difference was not observed for AAVs (Table 3, P ¼ 0.5479). Thus, no evidence was found that more indolent cancer was being diagnosed in younger AAVs. AAVs aged 40 to 54 years were less likely than WVs aged 40 to 54 years in our cohort to meet active surveillance criteria (Table 1, P ¼ 0.0340) [19]. Specifically, young AAVs had Z3 positive cores as the most common reason
SEER
Current cohort
1999–2006 322,840 (43,891/278,949) 13.6 6 4 79 80
2000–2007 2,050 (1,045/1,005) 51 2.6 2.4 93.5 93.9
not to qualify for active surveillance (Table 1, P ¼ 0.0229). Although higher grade and high prebiopsy PSA levels were used to disqualify a few more young AAVs than young WVs from active surveillance candidacy, these factors were not significantly different between races in the 40- to 54-years age group. Large active surveillance trials have limited outcome data on AA men [32–34]. In addition to our findings, prior evidence showed AA men meeting active surveillance criteria who underwent surgery are more likely to have higher rates of Gleason upscoring, lower rates of organ-confined disease, greater volume of cancer, greater likelihood of multifocality and transition zone cancers, higher hazard risks of biochemical recurrence, and positive surgical margins at prostatectomy. These findings from other studies also support our position that earlier PSA testing in AA men is not detecting more indolent cancer [31–34]. Rather, earlier PSA testing in AA men appears to diagnose more AA men with prostate cancer at a potentially curable stage. Comparisons of AAVs in the younger and older age groups suggest that if PSA testing is delayed to Z55 years, prostate cancers detected will have more unfavorable characteristics including higher grade, bilateral disease, and clinical stage (Table 3). Our study has limitations. This is a retrospective review of administrative data selected for the absence of incident heart disease and oversampled for depression [35]. We acknowledge that we were unable to account for socioeconomic status, education levels, or family history of patients with prostate cancer, which are known to be associated with prostate cancer outcomes [3,6,10]. We did not account for veterans using 5α-reductase inhibitors or statins or for those receiving additional care outside the VHA. Although we have used the VHA as a model of equal care without screening biases, this is not a perfect assumption as even within this system there are issues with access to care. PSA recommendations are changing rapidly [13,36–38], and a cutoff of 4 ng/ml and screening for men between the ages of 40 and 70 years may not be reflective of today's clinical practice. Biopsy data regarding number of positive cores and total number of cores in WV were less commonly reported for WVs than for AAVs and may have influenced our results.
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We acknowledge that the large screening trial populations where o5% of men participating were AA [36,37] and the VHA cohort presented here are different. When the U.S. Preventive Services Task Force [38] issued recommendations about PSA testing based on the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and European Randomised Study of Screening for Prostate Cancer (ERSPC) study [36,37], we were concerned that AA men in general were being counseled on the risks and benefits of PSA testing based on data from a study group of largely white men of European descent with no account for differences in the prostate cancer disease process in AA men. We believe that our cohort provides new and important information to AA men regarding the pros/cons of PSA testing. In summary, comparative statistics between AAVs and WVs aged 55 to 70 years confirmed previously reported disparate outcomes between races. AAVs aged 55 to 70 years were more likely than WVs aged 55 to 70 years to have higher prebiopsy PSA levels, higher clinical stage at diagnosis, and greater likelihood of bilateral disease (Table 2). When AAVs and WVs aged 40 to 54 years were compared, these differences were mitigated. No racial differences in prebiopsy PSA levels, tumor grade, or clinical stage at diagnosis were noted for veterans aged 40 to 54 years.
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