IS HISPANIC RACE AN IMPORTANT PREDICTOR OF TREATMENT FAILURE FOLLOWING RADICAL PROSTATECTOMY FOR PROSTATE CANCER?

IS HISPANIC RACE AN IMPORTANT PREDICTOR OF TREATMENT FAILURE FOLLOWING RADICAL PROSTATECTOMY FOR PROSTATE CANCER?

0022-5347/04/1725-1856/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION Vol. 172, 1856 –1859, November 2004 Printed in U...

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0022-5347/04/1725-1856/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 172, 1856 –1859, November 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000141783.67470.55

IS HISPANIC RACE AN IMPORTANT PREDICTOR OF TREATMENT FAILURE FOLLOWING RADICAL PROSTATECTOMY FOR PROSTATE CANCER? JOHN S. LAM, JOSHUA D. SCLAR, MANISHA DESAI, MAHESH M. MANSUKHANI, MITCHELL C. BENSON AND ERIK T. GOLUBOFF* From the Departments of Urology (JSL, JDS, MCB, ETG), Biostatistics (MD) and Pathology (MMM), Columbia University, New York, New York

ABSTRACT

Purpose: Hispanic-Americans are the fastest growing minority group in the United States. Many studies have compared prostate cancer treatment outcomes between black and white men, but few such studies have been done with Hispanic men. We compared clinical and pathological features as well as the treatment failure rate of radical prostatectomy in contemporaneously treated groups of Hispanic and white men with prostate cancer. Materials and Methods: Between 1995 and 2002, 136 Hispanic men and 315 white men underwent radical prostatectomy. Treatment failure was defined as having a prostate specific antigen (PSA) of 0.2 or greater more than 8 weeks after surgery or receiving any adjuvant therapy. Known predictors of failure and race were evaluated for their ability to predict treatment failure. Results: Median followup was 32 months for Hispanic and 36 months for white patients. Hispanic men were older, had a higher percentage of abnormal rectal examinations, Gleason 7 tumors and preoperative PSA levels greater than 10. Preoperative PSA, specimen Gleason score, pathological stage and surgical margin were all strongly associated with treatment failure (p ⬍0.001). Despite differences in clinical characteristics, overall failure rates did not differ between Hispanic and white men (18.7% vs 17.8%). The odds ratio for treatment failure for Hispanic relative to white men after adjusting for the previously mentioned risk factors was 0.87 (95% CI [0.44, 1.68], p ⫽ 0.670). Conclusions: This study shows that Hispanic race does not influence the treatment failure rate of radical prostatectomy in contemporaneously treated patients with prostate cancer at 1 institution. To our knowledge this study represents the largest of its kind, but longer followup and other confirmatory studies are needed. KEY WORDS: Hispanic Americans, outcome assessment, prostatectomy, prostatic neoplasms

In 2000 approximately 35.3 million Hispanics comprised about 12.5% of the total United States population, having increased from 9% of the population in 1990, making them the nation’s fastest growing population.1 According to the Census Bureau this population will reach 96 million by 2050.1 An estimated 8,500 Hispanic men were diagnosed with prostate cancer and 1,200 deaths were estimated to have resulted from this disease in 2003, making it the most commonly diagnosed cancer and the second leading cause of cancer death among Hispanic men.2 Currently there are limited data on clinical presentation and treatment outcomes in Hispanic men with prostate cancer. Studies have shown that Hispanic men with prostate cancer present with more advanced stage tumors, higher serum prostate specific antigen (PSA) levels and higher grade tumors compared to white men.3–7 Several studies have looked at differences in outcome after radical prostatectomy for clinically localized prostate cancer between black and white men, however to our knowledge none have made such comparisons to Hispanic men.8 –14 To compare outcomes after radical prostatectomy between these 2 groups, the clinical and pathological features of Hispanic

and white men who underwent radical prostatectomy were retrospectively reviewed. Preoperative factors including Hispanic race were evaluated for ability to predict outcome, specifically to determine whether Hispanic race was an important predictor of treatment failure following radical prostatectomy after adjusting for clinical features. MATERIALS AND METHODS

Patient charts and computerized records were retrospectively reviewed for Hispanic-American and white men who had consecutively undergone radical retropubic prostatectomy for clinically localized prostate cancer between July 1995 and November 2002 at our institution by 1 of the 2 investigators (MCB, ETG). A total of 462 men were identified, and 11 patients were excluded from study because they received preoperative androgen deprivation therapy (9) or radiation therapy (2). This exclusion resulted in a study population of 451 consecutive men, of whom 136 were Hispanic and 315 were white. Ethnicity was defined by patient self-characterization as recorded in demographic data collected at registration. Choices for ethnic characterization included Hispanic, white non-Hispanic, Asian, black and other. All men underwent complete evaluation including history and physical examination, digital rectal examination (DRE) and serum PSA measurement. Serum PSA determinations were done with the monoclonal Hybritech Tandem-R

Accepted for publication May 14, 2004. * Correspondence: Department of Urology, Columbia University College of Physicians and Surgeons, Allen Pavilion, New York-Presbyterian Hospital, 5141 Broadway, New York, New York 10034 (telephone: 212932-4309; FAX: 212-932-4448; e-mail: [email protected]). 1856

HISPANIC RACE AS PREDICTOR OF FAILURE AFTER RADICAL PROSTATECTOMY

total PSA assay (Hybritech, San Diego, California) and were obtained before any treatment or DRE. All men had biopsy confirmed prostate cancer. Preoperative PSA (prePSA), age, race, clinical stage, biopsy and specimen Gleason score, pathological stage, specimen prostate volume, calculated specimen PSA density, seminal vesicle involvement, surgical margin status and lymph node status were recorded for each patient in a computerized database. Patients were staged according to the 1997 TNM staging system and tumors were graded according to the Gleason grading system. Pathological examination was performed in a standard fashion. PSA was measured 6 to 8 weeks after surgery and every 3 to 6 months thereafter. Treatment failure was defined as having a PSA of 0.2 ng/ml or greater 8 weeks or longer after surgery, or receiving any adjuvant therapy. Adjuvant therapies included radiation and/or hormones, and were given at the discretion of the surgeon based on pathological analysis of the radical prostatectomy specimen. The Student’s t test was used to compare mean values of continuous variables between the 2 races. Comparisons between the 2 groups were made using the chi-square test to examine possible racial differences in distributions of categorical variables such as prostate biopsy Gleason sum, pathological stage, specimen Gleason sum, as well as the incidence of positive surgical margins and positive pelvic lymph nodes. All p values resulted from the use of 2-sided hypothesis tests. To obtain an estimate of the odds ratio after adjusting for preoperative clinical features such as age, serum PSA, clinical stage and biopsy Gleason score, we fit a multivariate logistic regression model regressing failure on an indicator for whether the patient was Hispanic as well as prespecified covariates. There were 3 patients missing data on whether they had treatment failure (2 of whom were Hispanic) who were included in the description of disease characteristics but excluded from the analysis assessing the influence of race on failure. The Cox proportional hazards regression model was used to model the hazard ratio of treatment failure for Hispanic men versus white men. The outcome for this analysis was months from surgery until failure, where failure is defined as the first increased PSA of 0.2 ng/ml after surgery. For those in whom treatment did not fail during observation the out-

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come was the time from surgery until the last PSA measurement. Data from those in whom treatment did fail during followup were considered censored observations since we do not know the exact failure time. Those patients who received adjuvant therapy immediately after radical prostatectomy (29) were included in the analysis as a time to failure of 0 months. RESULTS

A total of 451 men (136 Hispanic and 315 white men) underwent radical prostatectomy for prostate cancer. The distribution of surgeries performed each year was similar between Hispanic and white men. Median followup was 32 months for Hispanic patients and 36 months for white patients. Mean age was significantly higher in Hispanic men than in white men (62 vs 59 years, p ⬍0.01). A greater proportion of Hispanic men than white men presented with an abnormal DRE (40.4% vs 32.4%). The distribution of prePSA levels differed significantly between the 2 groups (p ⫽ 0.0401). A greater percentage of Hispanic men than white men presented with a prePSA greater than 10 ng/ml (22.8% vs 13.3%). Biopsy Gleason sum distribution also differed between the 2 groups (p ⫽ 0.0488). A greater percentage of Hispanic men than white men presented with Gleason 7 disease (37.5% vs 26.0%). Despite these findings the pathological examination of surgical specimens revealed no significant differences between the 2 groups (table 1). Despite differences in clinical presentation, treatment failure rates were similar between Hispanic men (18.7%) and Caucasian men (17.8%, p ⫽ 0.942). Logistic regression analysis revealed that higher prePSA, postoperative Gleason scores, pathological stages, positive surgical margins and positive lymph nodes were strongly associated with treatment failure (p ⬍0.001). Positive surgical margins were not associated with race (p ⫽ 0.2671). There was no significant difference in mean age between men in whom treatment failed and those in whom it did not (61 vs 60 years, p ⫽ 0.3968, table 2). The distribution of type of failure was comparable between the 2 groups (p ⫽ 0.4582). Of the 56 white men in whom treatment failed, 39.3% was due to receiving adjuvant therapy, 23.2% because of increased PSA but receiving no further

TABLE 1. Clinical and pathological features of Hispanic and white men undergoing radical prostatectomy Hispanic No. pts 136 Mean age at surgery ⫾ SD 61.96 ⫾ 7.22 No. ng/ml prePSA distribution (%): Less than 4 20 (14.7) 4–10 85 (62.5) Greater than 10 31 (22.8) No. biopsy Gleason score frequency (%): 6 or Less 76 (55.9) 7 51 (37.5) 8–10 9 (6.6) No. clinical stage frequency (%): T1 81 (59.6) T2 55 (40.4) T3 0 (0) No. specimen Gleason score frequency (%):‡ 6 or Less 47 (34.6) 7 73 (53.7) 8–10 16 (11.8) No. pathological stage frequency (%): T2 93 (68.4) T3a (capsular penetration) 33 (24.3) T3b (seminal vesicle invasion) 7 (5.1) T4 3 (2.2) No. pos surgical margin frequency (%) 38 (27.9) No. pos lymph nodes frequency (%) 2 (1.5) * Student’s t test or chi-square test comparing Hispanic and white men. † For comparison between patients with T1 and T2 disease. ‡ Single white specimen not assigned Gleason score due to atypical histological features.

Caucasian 315 59.45 ⫾ 7.02

p Value* ⬍0.01 0.0401

47 (14.9) 226 (71.7) 42 (13.3) 0.0488 210 (66.7) 82 (26.0) 23 (7.3) 0.0819† 213 (67.6) 100 (31.7) 2 (0.6) 0.1649 136 (43.2) 139 (44.1) 39 (12.4) 0.9651 213 (67.6) 78 (24.8) 18 (5.7) 5 (1.6) 71 (22.5) 4 (1.3)

0.2671 0.7818

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HISPANIC RACE AS PREDICTOR OF FAILURE AFTER RADICAL PROSTATECTOMY TABLE 2. Estimates from logistic regression analysis

Univariate: Hispanic race Multivariate: Hispanic race Age PrePSA: 4–10 Vs 0–4 More than 10 vs 0–4 Specimen Gleason score: 7 Vs 6 or less 8–10 Vs 6 or less Pathological stage: T3a Vs T2 T3b Vs T2 T4 Vs 12 Pos surgical margins Pos lymph nodes

OR

95% CI

p Value

1.06

0.63–1.78

0.836

0.87 0.97

0.44–1.68 0.93–1.02

0.670 0.259

0.64 1.77

0.26–1.56 0.66–4.76

1.60 8.81

0.75–3.43 3.55–21.88

1.15 7.58 1.44 7.94 2.29

0.56–2.38 2.38–24.15 0.20–10.22 3.95–15.95 0.23–22.60

⬍0.001 0.0068

⬍0.001 0.477

therapy, and 37.5% from an increased PSA and receiving salvage therapy. Similarly, of the 25 Hispanic men in whom treatment failed, 28% received adjuvant therapy, 20% had increased PSA levels but received no further treatment and 52% received salvage therapy due to an increased PSA. Furthermore, there were comparable proportions of Hispanic and white men who received adjuvant therapy (28% Hispanic vs 39% white) vs those in whom treatment failed due to an increased PSA (72% Hispanic vs 61% white, p ⫽ 0.467). The unadjusted odds ratio for treatment failure in Hispanic men relative to white men was 1.06 (95% CI [0.63, 1.78], p ⫽ 0.836), implying Hispanic race has no significant effect on outcome after radical prostatectomy without controlling for other factors. An estimate of the odds ratio adjusted for prePSA levels did not change this estimate significantly. The odds ratio for treatment failure in Hispanic men relative to white men after adjusting for all known risk factors was 0.87 (95% CI [0.44, 1.68], p ⫽ 0.670), indicating that the odds of failure do not differ by race after controlling for other risk factors (table 2). The Cox proportional hazards regression model yields an estimated unadjusted hazard ratio of 1.09 (95% CI 0.678, 1.74), indicating that the risk of treatment failure in Hispanic men relative to white men is not significantly different. In conclusion Hispanic race was not found to be predictive of failure after radical prostatectomy. DISCUSSION

Prostate cancer remains the most commonly diagnosed cancer and the second leading cause of cancer death among Hispanic-American men.1, 2 In addition, Hispanic men have been shown to present with more advanced stage disease compared to white men.3– 6 To our knowledge, all studies examining racial differences in prostate cancer detection and treatment outcome have so far focused on black men. Currently there are little data on whether clinical outcomes after radical prostatectomy differ in Hispanic men. At 12% of the United States population, the number of Hispanic-Americans nearly equals that of black men.1 Therefore, it is important that more data become available concerning outcomes following radical prostatectomy in this rapidly growing segment of society. Many studies have compared clinical and pathological features and failure after radical prostatectomy in black and white men, but this comparison has not been addressed in Hispanic men.9 –14 To our knowledge this series is the largest to date to examine the outcomes of Hispanic men (136) undergoing radical prostatectomy for prostate cancer. Although differences in clinical stage, age, biopsy Gleason score and serum prePSA were significant, the differences in pathological findings between Hispanic and white men were not.

Moreover, Hispanic race was not an independent predictor of treatment failure after radical prostatectomy. Although a recent study focused on the outcomes of Hispanic men who underwent radiotherapy for localized or locally advanced prostate cancer,15 no studies have looked at whether Hispanic race is an independent predictor of treatment failure after radical prostatectomy. In that study a higher percentage of Hispanic men had a PSA nadir of 1 ng/ml or greater after radiotherapy, and Hispanic men were reported to present with higher PSA and higher grade prostate cancer before treatment. However, this was a small retrospective study with only 54 Hispanic patients. In our study there were no differences in the incidence of high grade disease, positive surgical margins, nonorgan confined disease or seminal vesicle involvement between Hispanic and white men undergoing radical prostatectomy. In addition, Hispanic race was not a strong predictor for these adverse pathological findings. Hispanic men had higher prePSAs and Gleason grade tumors at diagnosis compared to white men, suggesting a diagnosis discrepancy or an intrinsic biological difference between these 2 groups. From the patient viewpoint health care access, lack of awareness, different lifestyle practices and health attitudes, embarrassment and distinct cultural perspectives, and/or language barriers are socioeconomic factors that could delay or prevent diagnosis. If indeed lifestyle characteristics and/or attitudes of Hispanic men tend to prevent proper prostate cancer diagnosis, targeted efforts are needed to increase awareness in this group of men. Tumor cell burden and/or disease virulence may be higher in Hispanic men at diagnosis. Serum androgen levels may also have a role in serum PSA levels in men with localized prostate cancer, however this has not been well studied in Hispanics. Variations in androgen metabolism genes may also contribute by increasing intraprostatic androgens, and although this is associated with an increased risk of prostate cancer in black and Hispanic men, its impact on serum PSA is unclear.16 In our study the mean age of Hispanic patients was also higher than that of white patients. Although this was clinically insignificant, the increased age in the Hispanic group may influence serum PSA levels. Serum PSA increases as men age due to the histological hyperplastic changes of the epithelial cells of the aging prostate.17 Increased PSA levels from aging prostates may also be due to prostatic ischemia or infarction, chronic subclinical prostatitis, prostatic intraepithelial neoplasia and loss of normal physiological barrier integrity.17 Despite having higher prePSAs and higher proportions of palpable lesions and Gleason 7 tumors, if stratified for known predictors of failure, there appears to be no difference in treatment outcomes between Hispanic and white men. These data suggest that early prostate cancer detection among Hispanic populations may improve prostate cancer characteristics and potentially improve treatment outcomes. In 1 study less than half of Hispanic men at risk received screening for prostate cancer either through a PSA test or DRE. In comparison at least 50% of white and black men at risk have undergone a PSA test or DRE in the last year.1 Using regression analysis Hispanic race was not an important predictor of outcome following radical prostatectomy after adjusting for relevant clinical features. Specimen Gleason score, pathological stage and surgical margin were all strongly associated with failure (p ⬍0.001), which is consistent with other recent studies that have examined disease-free survival after treatment for localized prostate cancer.12–14 A possible criticism of this study might be the possibility for errors in classifying who was Hispanic. In our study the method used was self-identification. In a study by Stewart et al self-identification had higher sensitivity, specificity, and positive and negative predictive value than registry, surname, registry surname, Generally Useful Ethnic Search

HISPANIC RACE AS PREDICTOR OF FAILURE AFTER RADICAL PROSTATECTOMY

System and a composite of these methods.18 Although our Hispanic study population was self-identified as Hispanic, the vast majority were also self-identified as from the Dominican Republic. It is possible that Hispanics of Dominican origin are different than Hispanics from other parts of the world, and may have different lifestyles, diets, health attitudes and genetic/biological properties. Future studies should be aimed at determining whether true biological differences exist in prostate cancers that develop in different ethnic groups, which may provide useful clues to cancer development and progression for all patients. Research into health services and attitudes among Hispanic patients may also help identify systematic problems that lead to later diagnosis. In the meantime efforts should be made to ensure that Hispanic men are made aware of their risk of prostate cancer. The limitations of the present study are that it is retrospective and that patients undergoing radical prostatectomy represent a select subset with newly diagnosed clinically localized tumors, often with favorable preoperative characteristics. This may not be representative of all patients with clinically localized prostate cancer. In addition, median followup was relatively short and, therefore, differences in cause specific, overall survival or biochemical failure may not yet be fully appreciated, although most failures after radical prostatectomy occur within 3 years of surgery.19 Investigators at other centers should assess and report their data on the matter. CONCLUSIONS

This study shows that in contemporaneously treated groups of Hispanic and white men at the same institution, the clinical outcome following radical prostatectomy is similar. The decision to pursue curative therapies such as radical prostatectomy should be based on the same preoperative clinical factors presently used for all patients. To our knowledge this is the largest comparison of surgically treated prostate cancers between these 2 groups. Prospective evaluation of whether Hispanic men are at increased risk for disease progression following radical prostatectomy is needed. In addition, improved screening and early detection of prostate cancer in the Hispanic community may improve results. REFERENCES

1. Grieco, E. M. and Cassidy, R. C.: Overview of race and Hispanic origin: 2000. Census 2000 Brief. U.S. Department of Commerce, Economics and Statistics Administration, U.S. Census Bureau, 2001. Available at http://www.census.gov/prod/ 2001pubs/c2kbr01–1.pdf. Accessed August 4, 2004 2. O’Brien, K., Cokkinides, V., Jemal, A., Cardinez, C. J., Murray, T., Samuels, A. et al: Cancer statistics for Hispanics, 2003. CA Cancer J Clin, 53: 208, 2003 3. Hoffman, R. M., Gilliland, F. D., Eley, J. W., Harlan, L. C., Stephenson, R. A., Stanford, J. L. et al: Racial and ethnic differences in advanced-stage prostate cancer: the Prostate Cancer Outcomes Study. J Natl Cancer Inst, 93: 388, 2001 4. Zietman, A., Moughan, J., Owen, J. and Hanks, G.: The Patterns of Care Survey of radiation therapy in localized prostate cancer: similarities between the practice nationally and in

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minority-rich areas. Int J Radiat Oncol Biol Phys, 50: 75, 2001 5. Danley, K. L., Richardson, J. L., Bernstein, L., Langholz, B. and Ross, R. K.: Prostate cancer: trends in mortality and stagespecific incidence rates by racial/ethnic group in Los Angeles County, California (United States). Cancer Causes Control, 6: 492, 1995 6. Delfino, R. J., Ferrini, R. L., Taylor, T. H., Howe, S. and Anton-Culver, H.: Demographic differences in prostate cancer incidence and stage: an examination of population diversity in California. Am J Prev Med, 14: 96, 1998 7. Lam, J. S., Desai, M., Mansukhani, M. M., Benson, M. C. and Goluboff, E. T.: Is Hispanic race an independent risk factor for pathological stage in patients undergoing radical prostatectomy? J Urol, 170: 2288, 2003 8. Fowler, J. E., Jr. and Terrell, F.: Survival in blacks and whites after treatment for localized prostate cancer. J Urol, 156: 133, 1996 9. Moul, J. W., Douglas, T. H., McCarthy, W. F. and McLeod, D. G.: Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J Urol, 155: 1667, 1996 10. Powell, I. J., Heilburn, L. K., Sakr, W., Grignon, D., Montie, J., Novallo, M. et al: The predictive value of race as a clinical prognostic factor among patients with clinically localized prostate cancer: a multivariate analysis of positive surgical margins. Urology, 49: 726, 1997 11. Sohayda, C. J., Kupelian, P. A., Altsman, K. A. and Klein, E. A.: Race as an independent predictor of outcome after treatment for localized prostate cancer. J Urol, 162: 1331, 1999 12. Eastham, J. A. and Kattan, M. W.: Disease recurrence in black and white men undergoing radical prostatectomy for clinical stage T1–T2 prostate cancer. J Urol, 163: 143, 2000 13. Moul, J. W., Connelly, R. R., Lubeck, D. P., Bauer, J. J., Sun, L., Flanders, S. C. et al: Predicting risk of prostate specific antigen recurrence after radical prostatectomy with the Center for Prostate Disease Research and Cancer of the Prostate Strategic Urologic Research Endeavor databases. J Urol, 166: 1322, 2001 14. Freedland, S. J., Amling, C. L., Dorey, F., Kane, C. J., Presti, J. C., Jr., Terris, M. K. et al: Race as an outcome predictor after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Urology, 60: 670, 2002 15. Rosser, C. J., Kuban, D. A., Levy, L. B., Pettaway, C. A., Chichakli, R., Kamat, A. M. et al: Clinical features and treatment outcome of Hispanic men with prostate cancer following external beam radiotherapy. J Urol, 170: 1856, 2003 16. Makridakis, N. M., Ross, R. K., Pike, M. C., Crocitto, L. E., Kolonel, L. N., Pearce, C. L. et al: Association of mis-sense substitution in SRD5A2 gene with prostate cancer in AfricanAmerican and Hispanic men in Los Angeles, USA. Lancet, 354: 975, 1999 17. Stamey, T., Yang, N., Hay, A., McNeal, J. E., Freiha, F. S. and Redwine, E.: Prostate specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med, 317: 909, 1987 18. Stewart, S. L., Swallen, K. C., Glaser, S. L., Horn-Ross, P. L. and West, D. W.: Comparison of methods for classifying Hispanic ethnicity in a population-based cancer registry. Am J Epidemiol, 149: 1063, 1999 19. Partin, A. W., Pearson, J. D., Landis, P. K., Carter, H. B., Pound, C. R., Clemens, J. Q. et al: Evaluation of serum prostate– specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology, 43: 649, 1994