Racial and geographic differences in prostate ... - Wiley Online Library

Int. J. Cancer (Radiat. Oncol. Invest): 96, 363–371 (2001) © 2001 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

Changing Face and Different Countenances of Prostate Cancer: Racial and Geographic Differences in Prostate-specific Antigen (PSA), Stage, and Grade Trends in the PSA Era Ashesh B. Jani, M.D.,1 Florin Vaida, Ph.D.,2 Gerald Hanks, M.D.,3 Suscha Asbell, M.D.,4 Oliver Sartor, M.D.,5 Judd W. Moul, M.D.,6 Mack Roach 3rd, M.D.,7 David Brachman, M.D.,8 Urmi Kalokhe, M.D.,9 Renate Muller-Runkel, Ph.D.,9 Paul Ray, D.O.,10 Lani Ignacio, R.N., B.S.N.,1 Azhar Awan, M.D.,1 Ralph R. Weichselbaum, M.D.,1 and Srinivasan Vijayakumar, M.D.1,11* 1 Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 2 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 3 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 4 Department of Radiation Oncology, Albert Einstein Medical Center, Philadelphia, Pennsylvania 5 Department of Medical Oncology, Louisiana State University, New Orleans, Louisiana 6 Department of Surgery, Uniformed Services University, and Walter Reed Army Medical Center, Bethesda, Maryland 7 Department of Radiation Oncology, University of California, San Francisco, California 8 Arizona Oncology Services, Phoenix, Arizona 9 Oncology Center, St. Margaret’s Hospital, Hammond, Indiana 10 Department of Urology, Cook County Hospital, Chicago, Illinois 11 Department of Radiation Oncology, University of Illinois at Chicago, Chicago, Illinois. SUMMARY The purpose of this investigation was to examine changes in pretreatment prostate-specific antigen (PSA), stage, and grade over the past decade as a function of race and geographic region. A multiinstitutional database representing 6,790 patients (1,417 African-American, 5,373 white) diagnosed with nonmetastatic prostate cancer between 1988 and 1997 was constructed. PSA, stage, and grade data were tabulated by calendar year and region, and time trend analyses based on race and region were performed. There was an overall decline of PSA of 0.8%/year, which was significant (P = 0.0001), with a faster rate of decline in African-Americans (1.9%/year) than for whites (0.6%/year). The odds ratio (OR) for a stage shift was 1.09, which was significant (P < 0.0001), and this shift was greater in whites. The OR for an overall grade shift was 1.15, which was significant (P < 0.0001). Although grade and PSA trends were similar for the different regions, there were significant regional differences in stage trends. The implications are that the face of prostate cancer has changed over the past decade; i.e., the distributions of stage, grade, and PSA (the most important prognosticators) have changed. In addition, the countenances of that face are different for whites and African-Americans. For African-Americans, this is good news: the stage, grade, and PSA distributions are more favorable now than before. For whites, the trends are more complex and more dependent on region. These *Correspondence to: Srinivasan Vijayakumar, M.D., Department of Radiation Oncology, University of Illinois at Chicago, 1801 W. Taylor St., C400, Chicago, IL 60612. Phone: (312) 413-0249; Fax: (312) 413-8686; E-mail: vijay@jasmine. rado.uic.edu Received 16 April 2001; Revised 17 July 2001; Accepted 19 July 2001 Published online 4 September 2001

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Jani et al.: PSA, Stage, and Grade Trends

findings should be used for future clinical and health-policy decisions in the screening and treatment of prostate cancer. © 2001 Wiley-Liss, Inc.

Key words: prostate cancer; prostate-specific antigen; stage; grade; race; time trends

INTRODUCTION Adenocarcinoma of the prostate represents one of the most common cancer diagnoses for which health-care intervention is performed in the United States. Although there appears to be a decline in the incidence after the dramatic increase during the early 1990s [1,2], the high incidence has nonetheless increased public awareness of the diagnosis. The increase in incidence in recent years has been hypothesized to result partly from the availability and application of a relatively sensitive and specific screening test, prostate-specific antigen (PSA). Although the optimum role of PSA for prostate cancer screening remains a subject of controversy [3], PSA has an established role in the detection of prostate cancer and appears to have caused a decrease in distant metastases in the screened population [4]. In addition to its use in screening, PSA has a definitive role in determining outcome after intervention [4,5]. Indeed, PSA level has been approved by the Food and Drug Administration as an aid for the determination of prognosis and management and for the detection of prostate cancer in men aged 50 or older [6]. Clearly, PSA will continue to occupy an important role for prostate cancer diagnosis and management in any health-care delivery system. The use of PSA as a screening tool has changed the patterns of care, with needle biopsy becoming the predominant first step in diagnosing prostate cancer compared with the past when transurethral prostatectomy (TURP) was the most common method [7]. This has influenced the characteristics of the population diagnosed with prostate cancer over the past decade, and hence, efforts are needed to examine trends in patient and tumor characteristics in the era of PSA-based screening. There has been an increase in incidence during the PSA era, part of which is likely due to increased diagnosing of prevalent cases, as evidenced by a more recent decline [8]. This led to a shift to earlier stage at diagnosis, as well as diagnosis of so-called indolent cases [9]. The lead-time and length-time biases introduced by PSA-based diagnosis have been examined in only a few studies [8,10]. The Surveillance, Epidemiology, and End Results (SEER) program [11] found a decline in the inci-

dence of distant-stage disease during the PSA era, with resulting increases in cause-specific and overall survival, and, as indicated before, an increase then a decrease in the incidence of prostate cancer [11–13]. There was also a significant increase in the incidence of localized-stage and low- and intermediate-grade tumors. These initial studies looking at the influence of PSA-based diagnosing suggest changes in incidence, stage, and grade distributions during the PSA era. The SEER analyses, while important in adding to the understanding of changes in these parameters, did not, however, examine PSA trends. African-Americans have the highest incidence of prostate cancer in the world, and significant white–black differences in the incidence, patterns of care, and outcomes exist in the United States. However, the influence of PSA-based diagnosis upon prostate cancer stage, grade, and PSA patterns among African-Americans has not been addressed in the SEER studies described above, although a small single-institution study [14] found that PSA, grade, and stage shifted more for African-Americans than for whites over an 8-year period as a consequence of screening. PSA-era racial differences are likely since differences in absolute PSA level between whites and AfricanAmericans in both patients without [15] and patients with [16–18] prostate cancer have been observed. African-Americans present at a more advanced stage than whites [19], including in the setting of a military/equal-access health-care environment [20,21]. There has also been a stage-for-stage tumor volume disparity between whites and African-Americans in careful radical prostatectomy pathological assessment series during the PSA era [22]. PSA disparity was also found in a multiinstitutional Radiation Therapy Oncology Group (RTOG) study [23], African-Americans with nonmetastatic prostate cancer having a higher serum PSA level at diagnosis than whites. In both the RTOG study and a University of Chicago study [24], racial PSA differences were associated with socioeconomic indicators: income, education, and insurance status. Thus far, studies show that (1) more prostate cancers are diagnosed by PSA screening and needle biopsy than before (and this has led to changes in


Table 1.

Characteristics of Study Patient Populations from Participating Institutions Race Number

Midwest U of C WMH LGH MRH SMH Total South LSU East AEMC FCCC Total West ARIZ UCSF Total Military WRAMC All sites

365

White

Stage AA

T1

T2

Grade T3/4

I

II

III

NA

205 83 254 445 255 1,242

115 74 251 72 237 749

90 9 3 373 18 493

64 32 116 98 53 363

117 40 125 230 150 662

24 11 13 117 52 217

17 21 62 16 228 344

165 53 124 313 15 670

11 4 12 40 5 72

12 5 56 76 7 156

835

541

294

222

595

18

303

373

76

83

266 1,154 1,420

118 1,047 1,165

148 107 255

87 384 471

139 613 752

40 157 197

62 182 244

162 878 1,040

34 94 128

8 0 8

1,880 483 2,363

1,845 393 2,238

35 90 125

560 149 709

692 211 903

628 123 751

366 63 429

1,347 345 1,692

155 56 211

12 19 31

930 6,790

680 5,373

250 1,417

53 1,818

774 3,686

103 1,286

175 1,495

453 4,228

37 524

265 543

U of C ⳱ University of Chicago Hospitals (Chicago, IL); WMH ⳱ Weiss Memorial Hospital (Chicago, IL); LGH ⳱ LaGrange Hospital (LaGrange, IL); MRH ⳱ Michael Reese Hospital (Chicago, IL); SMH ⳱ St. Margaret’s Hospital (Hammond, IN); LSU ⳱ Louisiana State University (New Orleans, LA); AEMC ⳱ Albert Einstein Medical Center (Philadelphia, PA); FCCC ⳱ Fox Chase Cancer Center (Philadelphia, PA); ARIZ ⳱ Arizona Oncology Services (Phoenix, AZ); UCSF ⳱ University of California (San Francisco, CA); WRAMC ⳱ Walter Reed Army Medical Center (Washington, DC); NA ⳱ not available; AA ⳱ African-American.

the disease profile at diagnosis), (2) PSA level at diagnosis is a very strong prognostic factor, and (3) racial differences in the patterns of care and disease profile exist, including a higher PSA stage-forstage among African-Americans. The unknowns are (1) whether any stage, grade, and PSA distribution trends have occurred over the past decade within the nonmetastatic population, which constitutes approximately 85% to 90% of all cases diagnosed in recent years; (2) any differences between whites and African-Americans among these trends; and (3) geographic differences within the United States. These trends will have a significant influence on our understanding of prostate cancer from public-health, clinical-care, public-policy, resource-distribution, and research-focus perspectives. Our objective was to perform a multiinstitutional, geographically dispersed, pooled analysis to answer the issues raised above. Our hypothesis was that the stage, grade, and PSA distributions have changed over time (i.e., a change in the face of prostate cancer) and that there are likely geographic and racial differences (i.e., a change in the countenances of prostate cancer). To undertake this study, several institutions in each of the major geographic regions in the continental United States with an established database were approached to provide data that allowed for the construction of a multiin-

stitutional database. The large number of patients in the multiinstitutional database enabled increased statistical power to make more definitive conclusions about PSA, stage, and grade trends than any single institutional database. MATERIALS AND METHODS Table 1 shows the characteristics (race, stage, and grade) of the nonmetastatic study patient populations from the participating institutions as a function of site. It also shows the geographic region grouping of the participating institutions. As the table demonstrates, the data were taken from multiple institutions representing different geographic regions in the United States. Furthermore, different practice patterns, i.e., university/academic centers, private practice/community centers, and a military/ equal-access center, are represented. Using the information in Table 1 and the diagnosis date (i.e., the date of biopsy), a comprehensive database was constructed and used for analyses of trends in pretreatment PSA, stage, and grade. Pretreatment PSA Analyses The mean pretreatment PSA by calendar year was charted for the entire group and by race subgroup and geographic region (Table 2a). The following analyses were performed using the logarithm of the

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Table 2.

PSA, Stage, and Grade Information by Calendar Year and Race 1987– 1988

1989

1990

1991

1992

(a) Mean PSA by calendar year and race White n 145 277 393 606 837 PSA 9.78 8.16 10.99 9.31 9.45 AA n 51 53 98 136 183 PSA 22.48 12.53 14.52 13.10 14.46 All n 196 330 491 742 1,020 PSA 12.14 8.75 11.62 9.91 10.20 (b) Number (percentage) of patients in each stage by calendar year and race White n 145 277 393 606 837 T1/A 43 (30) 63 (23) 101 (26) 164 (27) 256 (31) T2/B 83 (57) 184 (66) 254 (65) 368 (61) 513 (61) T3-4/C 19 (13) 30 (11) 38 (9) 74 (12) 68 (8) AA n 51 53 98 136 183 T1/A 19 (37) 12 (23) 23 (24) 38 (28) 32 (18) T2/B 27 (53) 35 (66) 62 (63) 73 (54) 123 (67) T3-4/C 5 (10) 6 (11) 13 (13) 25 (18) 28 (15) All n 196 330 491 742 1020 T1/A 62 (32) 75 (23) 124 (25) 202 (27) 288 (28) T2/B 110 (56) 219 (66) 316 (64) 441 (59) 636 (63) T3-4/C 24 (12) 36 (11) 51 (11) 99 (14) 96 (9) (c) Number (percentage) of patients in each grade by calendar year and race White n 108 216 303 520 798 Grade I 32 (30) 81 (38) 115 (38) 177 (34) 235 (29) Grade II 65 (60) 125 (58) 173 (57) 311 (60) 509 (64) Grade III 11 (10) 10 (4) 15 (5) 32 (6) 54 (7) AA n 30 31 63 100 173 Grade I 14 (47) 7 (22) 17 (27) 28 (28) 34 (20) Grade II 13 (43) 22 (71) 39 (62) 66 (66) 118 (68) Grade III 3 (10) 2 (7) 7 (11) 6 (6) 21 (12) All n 138 247 366 620 971 Grade I 46 (33) 88 (35) 133 (36) 205 (33) 269 (27) Grade II 78 (57) 147 (60) 212 (58) 377 (61) 627 (65) Grade III 14 (10) 12 (5) 22 (6) 38 (6) 75 (8)

1993

1994

1995

1996

1997– 1998

753 8.78

748 9.06

591 8.96

548 9.24

475 8.23

224 10.93

244 12.05

199 13.25

167 12.64

62 8.05

977 9.23

992 9.72

790 9.89

715 9.94

537 8.21

753 205 (27) 439 (58) 109 (15)

748 216 (29) 390 (52) 142 (19)

591 159 (27) 249 (42) 183 (31)

548 135 (25) 233 (43) 180 (32)

475 141 (30) 123 (26) 211 (44)

224 42 (19) 138 (61) 44 (20)

244 42 (17) 163 (67) 39 (16)

199 60 (30) 105 (53) 34 (17)

167 47 (28) 92 (55) 28 (17)

62 20 (32) 32 (52) 10 (16)

977 247 (25) 577 (59) 153 (16)

992 258 (26) 453 (46) 181 (18)

790 219 (28) 354 (45) 217 (27)

715 182 (25) 325 (45) 208 (30)

537 161 (30) 155 (29) 221 (41)

730 190 (26) 478 (65) 62 (9)

731 166 (23) 495 (68) 70 (9)

574 102 (17) 422 (74) 50 (9)

537 79 (15) 399 (74) 59 (11)

468 65 (14) 369 (79) 34 (7)

219 57 (26) 138 (63) 24 (11)

237 50 (21) 160 (68) 27 (11)

187 26 (14) 140 (75) 21 (11)

161 14 (9) 136 (84) 11 (7)

61 6 (10) 50 (82) 5 (8)

949 247 (26) 616 (65) 86 (9)

968 216 (22) 655 (68) 97 (10)

761 128 (17) 562 (74) 71 (9)

698 83 (12) 535 (78) 70 (10)

529 71 (13) 419 (79) 39 (8)

PSA values are in nanograms per milliliter. AA ⳱ African-American.

PSA (which more closely approaches a Gaussian distribution than the actual PSA): (1) time-trend analyses for the PSA consisting of (a) analysis of the overall group and (b) subgroup analyses based on region, stage, grade, and race [in each case, the null hypothesis was that the log (PSA) time-trend curve has a slope of 0 (i.e., no change in PSA with time)]; (2) a test for a difference in PSA trends between African-Americans and whites [for this analysis, the null hypothesis was that the log (PSA) time-trend curves for both racial groups have the same slope]. The statistical test used for each of the above analyses was the t-test of regression.

Stage Shift Analyses Table 2b shows the number (and percentage) of patients in each stage by calendar year and race. Stage shift analyses, which are based on computation of the odds ratio (OR) for a shift to a higher stage, were performed using the information in this table. The following analyses were performed: (1) stage shift analyses consisting of (a) an analysis of the overall group and (b) subgroup analyses based on region and race [in each case, the null hypothesis was that the OR was 1.0 (i.e., that there was no stage shift with time), with an OR of > 1.0 repre-


senting a shift to a higher stage, and the statistical test used was the likelihood ratio test of multiple polytomous regression]; (2) a test for a difference in stage shift between African-Americans and whites [for this analysis, the null hypothesis was that both groups have the same stage shift with time, and the corresponding statistical test was also a likelihood ratio test of multiple polytomous regression, with an additional variable (race)]. Grade Shift Analyses Table 2c shows the number (and percentage) of patients in each grade by calendar year and race. The methodology for the overall and subgroup grade shift analyses and for testing the difference in grade shift between racial groups was identical to that described above for the stage shift analyses. RESULTS PSA Trend Analyses Table 3a shows the results of the PSA trend analyses. The percent change per year (and 95% confidence intervals and corresponding P values) for the overall group is shown. In addition, the results of the subgroup analyses by region, stage, grade, and race are shown. There was an overall decline in pretreatment PSA of 0.8%/year for the time period examined, which was highly significant (P ⳱ 0.0001). The subgroup analysis by region demonstrated some geographic variations; in particular, a PSA decline was not demonstrated in the East (+0.3%/year, P ⳱ 0.61), and the PSA decline in the West (–0.5%/year, P ⳱ 0.12) did not reach statistical significance. However, the military site, which is situated in the East, demonstrated a PSA decline that was significant (–1.8%/year, P ⳱ 0.01). The subgroup analysis by stage revealed no PSA decline for patients with T1 tumors (+0.7%/year, P ⳱ 0.47); however, there were highly statistically significant PSA declines for T2 (–1.4%/year, P < 0.0001) and T3/4 (–4.1%/year, P < 0.0001) tumors, with a progressively greater rate of decline with higher T stage. A similar phenomenon occurred for grade: the subgroup analysis by grade revealed no PSA decline for patients with G1 tumors (+0.4%/year, P ⳱ 0.47), but there were statistically significant PSA declines for G2 (–1.6%/ year, P < 0.0001) and G3 (–2.7%/year, P ⳱ 0.01) tumors, with a progressively greater rate of decline with higher grade. The subgroup analysis by race showed that the rates of PSA decline were 1.9%/year for AfricanAmericans and 0.6%/year for whites, each of which

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Table 3. Results of Statistical Analyses for PSA, Stage, and Grade (a) PSA trend analyses Overall By region Military East Midwest South West By stage T1 T2 T3/4 By grade I II III By race African-American White

(b) Stage shift analyses Overall By region Military East Midwest South West By race African-American White

(c) Grade shift analyses

Percent change per year (95% CI)

P value for PSA decline

−0.8 (−1.3, −0.3)

0.0001

−1.8 (−3.3, −0.4) +0.3 (−0.8, +1.5) −2.2 (−3.3, −1.1) −3.5 (−5.2, −1.8) −0.5 (−1.3, −0.3)

0.01 0.61 0.0001