Epidemiology and Screening

Prostate Cancer:

10TH INTERNATIONAL PROSTATE CANCER UPDATE Prostate Cancer: Epidemiology and Screening Michael K. Brawer, MD,* E. David Crawford, MD,† Jackson Fowler, Jr, MD,‡ M. Scott Lucia, MD,† Fritz H. Schröeder, MD§ *Northwest Prostate Institute, Seattle; †University of Colorado Health Sciences Center, Denver; ‡University of Mississippi School of Medicine, Jackson; §Erasmus University, Rotterdam, the Netherlands The challenge continues—to find better methods of screening for prostate cancer, of determining who should undergo needle biopsy, and of predicting who will fail initial therapy. Investigators are looking at the value of neural networks and an array of markers to provide improved screening and prognostic information. Key words: Neoplasm staging • Prognosis • Prostatectomy • Prostate-specific antigen • Prostatic neoplasms T he wealth of information that can be gleaned from examination of prostate specimens obtained by needle biopsy and following radical prostatectomy underscores the importance of the urologist and the pathologist having an excellent working relationship. M. Scott Lucia, MD, stated that despite the dramatic increase in the ability to diagnose prostate cancer, in public awareness, and in the numbers of radical prostatectomies being performed, we are still severely limited in our ability to accurately predict in which patients this form of therapy will fail.1 Cancer Progression Prognosticators The most important and established prognosticators for prostatic carcinoma include the Gleason grade, the extent of tumor or tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy. Unfortunately, of these, only the Gleason grade can be determined reliably by examination of the needle biopsy specimens. It is well recognized that high-grade cancer, most particularly the percent of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression.2 Other studies, however, have demonstrated that low-grade tumors can be biologically aggressive.3-6 Of course, one is always mindful that the Gleason grade of the biopsy specimen may not reflect that of the radical prostatectomy specimen, with undergrading far more common than overgrading. Up to 50% of patients may be undergraded by examination of the needle biopsy specimens.7,8 Although tumor volume is difficult to ascertain based on preclinical parameters, it does remain an important prognostic variable.3,4,9 Data in the literature have suggested a reasonable correlation between the extent of tumor in biopsy specimens, the number of biopsy cores involved, and tumor volume.10-13 Larger tumors more often are associated with advanced grade and stage. Whether a tumor attaining a large size is the determinant of this biologic aggressiveness or whether tumors that are Supplement REVIEWS IN UROLOGY 5 Epidemiology/Screening continued intrinsically biologically aggressive become large is unknown. Miller and Cygan,14 for example, have demonstrated that there is a range of Gleason scores (2 to 10) in men with tumor volumes less than 0.5 cc. This suggests tumors may originate as high-grade lesions. Clinicians and patients alike are increasingly interested in excluding “insignificant” tumors—those with little likelihood of manifesting themselves during a patient’s lifetime. Epstein and associates10 and other researchers11-13,15-17 defined insignificant tumors as those less than 0.2 cc, with no areas of Gleason grade 4 or 5. This is based on a review of 500 clinical T2 radical prostatectomy specimens in which none of the 21 patients with these criteria had either capsular penetration or disease progression during a 5-year follow-up. In selecting radical prostatectomy specimens from 157 patients with T1c disease, they found that 16% of tumors would be considered insignificant.10 They were able to identify 73% of these men with insignificant tumors if the following criteria were used: stage T1c; prostate-specific antigen density (PSAD) less than 0.1 ng/mL per gram; no Gleason grade 4 or 5 on biopsy specimen; and cancer length less than 3 mm in only 1 biopsy core.10 Unfortunately, 10 of 63 cancers considered clinically significant were mischaracterized using these parameters, and these men would have been denied cu- rative therapy. Contrary findings have been reported by Elgamal and coworkers,18 who found 25% of significant T1c tumors had less than 3 mm of cancer present, and Thorson and colleagues,19 who noted that positive surgical margins were found in 22% of their patients who had less than 1 mm of tumor on biopsy. Although theoretically useful, repeated biopsy in men who are considered to have insignificant cancer has not been shown to provide significant identification of men who need therapy.20 This further underscores the major problem with needle biopsy, for both diagnosis and prediction of malignant potential: the profound effect of sampling error. Crawford and colleagues21 carried out a computer-based simulation of random sextant core biopsies on 59 whole-mount radical prostatectomy specimens. Table 1 shows the major findings: 13% of insignificant tumors were detected, and 48% of significant tumors were missed. Several groups have demonstrated that combining data on the number of positive biopsy results or amount of tumor on biopsy specimens with prostate-specific antigen (PSA) level, clinical stage, and Gleason grade can improve prediction of pathologically upstaged neoplasms.11-13 A number of markers, including p53 and p21, have been investigated. Significant heterogeneity of expression of the mutated form of p53 lessens our ability to identify this marker reliably on biopsy specimens. Similar concerns are associated with DNA ploidy analysis. There is controversy as to whether microvessel density, a histologic marker of tumor angiogenesis, can offer significant enhancement of the ability to predict prognosis. It does seem to be an independent predictor of pathologic stage.22,23 With regard to prognosis, Barth,24 Rubin,25 and Gettman26,27 and their coworkers did not show independent prognostic information. Silberman and associates28 determined that microvessel density provided useful stratifying information. Classic findings predicting progression based on biochemical disease-free survival, such as pelvic lymph node and seminal vesicle extension, remain important markers (Table 2). Their ability to offer unique, independent prognostic features, particularly when combined with the amount of Gleason grade 4 or 5 cancer, has been contested recently.2 The fact that up to 15% of patients who have pathologic organ-confined disease that progresses12,17,29 has been a confounding observation to students of this disease. Intraprostatic vessels may serve as a method of escape in this setting. For example, Bahnson and colleagues30 demonstrated intravascular invasion associated with a 4-fold greater risk of progression. These findings have been corroborated by others.31 Screening Tests Table 1 Detection Rates of 6 Computer-Simulated, Random Sextant Core Biopsies by Alternative Classifications of Significance Number detected (%) Number undetected (%) Totals Criterion A Significant (≥ 0.5 cc) Insignificant (< 0.5 cc) 11 (58) 8 (20) 8 (42) 32 (80) 19 40 Criterion B Significant (≥ 0.25 cc) Insignificant (< 0.25 cc) 15 (52) 4 (13) 14 (48) 26 (87) 29 30 Adapted from Crawford ED et al. J Urol. 1998.21 6 REVIEWS IN UROLOGY Supplement Professor Fritz Schröeder believes that the value of screening for prostate cancer is unproven and will await the results of ongoing randomized studies in the United States and Europe.32 He noted, however, that the recent decrease in US statistics of mortality from prostate cancer may suggest that aggressive early detection and treatment may be warranted. The best screening regimen, according to Dr Schröeder, is the method capable of detecting those cancers that constitute a significant risk to the patient, yet are still curable. The diagnostic tests leading to biopsy Epidemiology/Screening should be associated with high specificity (thus decreasing the number of negative biopsy results) as well as high sensitivity (avoiding missing important neoplasms). By using standard indications for biopsy (abnormality on digital rectal examination [DRE] or PSA test), only about 20% to 25% of men subjected to biopsy will have carcinoma detected. Based on data from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, the threshold for biopsy should be a PSA level higher than 3 ng/mL, and those men with a PSA lower than 1 ng/mL should be excluded from DRE. Racial Differences in PSA Jackson Fowler, Jr, MD, has been one of the major investigators of the effects of race in men with prostate cancer. In his extensive experience at the Veterans Affairs Medical Center in Jackson, Miss (a setting that has a 40% black population), there is more variability in PSA levels in blacks.33,34 Dr Fowler’s work has demonstrated that the racial variability in serum PSA level is not related to prostate volume.35 Dr Fowler’s team has investigated the incidence of high-grade prostatic intraepithelial neoplasia (PIN) in black and white men. They compared 411 black and 639 white men and identified PIN in 55% and high-grade PIN in 8.9%. High-grade PIN was identified in 13% of the blacks and 6% of the whites (P < .001). The median PSA level was significantly higher in men with high-grade PIN. The incidence of cancer on repeated prostate needle biopsies has been reported by numerous authorities to be quite high. Fowler and colleagues36 studied 298 consecutive men undergoing 1 repeated biopsy and found cancer in 42 (32%) of 133 blacks, compared with 38 (23%) of 165 whites. These differences did not achieve statistical significance. Fowler’s group has confirmed the findings of others37-40 that PSA levels tend to be higher in black men than in Table 2 Prostate Cancer Risk of Progression at 5 Years Pelvic lymph nodes Seminal vesicles Established capsular penetration Focal capsular penetration Organ-confined 95% 85% 48% 33% 9% - 13% From Epstein JI et al. J Urol. 199317; Stein A et al. J Urol. 1992.29 white men with clinically localized (T1c-T2) prostate cancer (Table 3). Fowler’s group has also clearly demonstrated that blacks have higher-grade carcinoma at diagnosis. They evaluated 222 black and 298 white men with clinically localized prostate cancer and PSA levels between 2.5 and 9.9 ng/mL.41 Cancer was detected in 47% of blacks and 33% of whites; it was found in a higher percentage of blacks with each percent of free-to-total PSA. For example, of those men who had a percent-free PSA (%fPSA) less than 25, cancer was detected in 53% of blacks and 41% of whites. In those men who had a %fPSA higher than 25, 32% of blacks compared with 13% of whites had cancer. Both of these differences were statistically significant. There was no racial difference in age, prostate volume, total PSA, PSAD, or %fPSA in those without cancer. In those with cancer, only %fPSA was higher in blacks, providing a statistically signifi- cant difference. This suggests that racial differences and cancer detection in patients stratified by %fPSA are related to more of the free form in blacks. Dr Fowler concluded that while the PSA levels are higher in black men without evidence of cancer than in white men, there is no compelling rationale to use different reference ranges based on race.42 He further noted cut points for %fPSA that are based on studies with predominantly white men may not be equally applicable to blacks. Neural Networks Recognition of the variable natural history of prostatic carcinoma coupled with the increasing number of variables being measured in hopes of providing prognostic information has often found traditional statistical methods lacking. Artificial neural networks have the potential advantage of identifying novel relationships between dif- Table 3 Race and PSA Level in Men With Local Stage Prostate Cancer Number of patients Age (y)* PSA (ng/mL)† Prostate volume (mL)† Biopsy Gleason score ≥ 7 Black men White men P value 271 69.2 ± 7.7 8.9 (5.9 - 16.6) 35 (25 - 48) 130 (48) 239 68.1 ± 6.8 6.6 (3.9 - 11) 32 (24 - 44) 93 (39) .08 < .0001 .06 .04 PSA, prostate-specific antigen. *Mean ± SD. † Median, 25th to 75th percentile. Supplement REVIEWS IN UROLOGY 7 Epidemiology/Screening continued ferent types of data in ways distinct from conventional logistic regression approaches. E. David Crawford, MD, reported on several projects (funded by the Institute for Clinical Research in Washington, DC) dedicated to applying artificial intelligence methodology to prostatic carcinoma. These studies have used multivariate statistical modeling and nomograms. Established nomograms, including the one devised by Partin and associates,43,44 provide useful information for groups. These nomograms present problems when dealing with the individual patient, however. Many markers, including imaging, reverse transcriptase–polymerase chain reaction assays, DNA ploidy, nuclear morphometry, p53 and other tumor suppressor genes, bcl-2, and angiogenesis of microvessel density, did not, in general, improve prognostic prediction for the individual patient. The neural networks provide a potential alternative approach, because they can deduce patterns in data that other approaches cannot. Neural networks are complex mathematical models, based on the neuronal relationships within the brain. Multiple neural network units (processors) are connected with communication channels to carry numeric data. These units operate only with their local data and on inputs from other connections. Generally, studies incorporate a training set to establish the neural network methodology, followed by validation and test sets. Crawford and colleagues evaluated 309 patients from their radical prostatectomy database. Of these, 85% had a pathologic stage of T3 or higher. The investigators used a training set of 50% of the database and a validation set of 40%. A test group (10%) was randomly selected from the database. Input variables included preoperative PSA levels; prior therapy; age; prostate volume determined by ultrasonography; clinical tumor, node, metastasis (TNM); number of positive biopsy results; and Gleason scores (both primary and sums). 8 REVIEWS IN UROLOGY Supplement With respect to prediction of pathologic stage, the artificial neural network achieved a sensitivity of 85% and a specificity of 57% for both the training and testing sets. Prediction of advanced and locally advanced disease shared an overall accuracy of 72%. Similar findings were observed with the validation cases, which demonstrated sensitivity and specificity of 79% and 81%, respectively, while accuracy for the validation set was 80%. In contrast, multivariate regression analysis for the validation cases demonstrated a sensitivity of 95% but a specificity of only 18%. The variables, in order of importance in predicting pathologic stage, were clinical stage (TNM), prior new adjuvant therapy, prostate size, percentage of biopsy tissue that was positive, DRE, presurgery PSA level, primary biopsy Gleason score 8, age, and total Gleason score of the biopsy specimens. With respect to prediction of biochemical failure, sensitivity and specificity for the neural networks were 43% and 92%, respectively, for the training and testing sets. The accuracy for detecting recurrence was 47%, while that for nonoccurrence was 91%. Accuracy in the training and testing cases was 85% for predicting recurrence. In contrast, multivariate regression analysis of the validation cases showed sensitivity and specificity of 0% and 97%, respectively. Dr Crawford concluded that the ability of artificial neural networks to use a variety of factors available in clinical use to ferret out relationships between parameters offers a useful adjuvant to our ability to ascertain the likely outcomes for patients with prostatic carcinoma. Advancement will occur with more variables and larger databases to establish these models. ■ References 1. Lucia MS. Pathology of the prostate. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 2. Stamey TA, McNeal JE, Yemoto CM, et al. Biological determinants of cancer progression in men with prostate cancer. JAMA. 1999;281:13951400. 3. McNeal JE, Villers AA, Redwine EA, et al. Histologic differentiation, cancer volume, and pelvic lymph node metastasis in adenocarcinoma of the prostate. Cancer. 1990;66:1225-1233. 4. Humphrey PA, Walther PJ, Currin SM, Vollmer RT. 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Thorson P, Arcangeli C, Keetch PA, Humphrey PA. Diagnostic features and follow-up of minimal carcinoma in prostate needle biopsies. Mod Pathol. 1997;10(91A):524. 20. Epstein JI, Walsh PC, Sauvageot J, Carter HB. Use of repeat sextant and transition zone biopsies for assessing extent of prostate cancer. J Urol. 1997; 158:1886. Epidemiology/Screening 21. Crawford ED, Hirano D, Werahera PN, et al. Computer modeling of prostate biopsy: tumor size and location—not clinical significance—determine cancer detection. J Urol. 1998;159:1260-1264. 22. Brawer MK, Deering RE, Brown M, et al. Predictors of pathologic stage in prostatic carcinoma: the role of neovascularity. Cancer. 1994;73:678687. 23. Bostwick DG, Wheeler TM, Blute M, et al. Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. Urology. 1996;48:47-57. 24. Barth PJ, Weingartner K, Kohler HH, et al. Assessment of vascularization in prostate carcinoma: a morphometric investigation. Hum Pathol. 1996;27:1306. 25. Rubin MA, Buyyounouski M, Bagiella E, et al. Microvessel density in prostate cancer: lack of correlation with tumor grade, pathologic stage, and clinical outcome. Urology. 1999;53:542-547. 26. Gettman MT, Bergstralh EJ, Blute M, et al. Prediction of patient outcome in pathologic stage T2 adenocarcinoma of the prostate: lack of significance for microvessel density analysis. Urology. 1998;51:79-85. 27. Gettman MT, Pacelli A, Slezak J, et al. Role of microvessel density in predicting recurrence in pathologic stage T3 prostatic adenocarcinoma. Urology. 1999;54:479-485. 28. Silberman MA, Partin AW, Veltri RW, Epstein JI. Tumor angiogenesis correlates with progression after radical prostatectomy but not with pathologic stage in Gleason sum 5 to 7 adenocarcinoma of the prostate. Cancer. 1997;79:772. 29. Stein A, deKernion JB, Smith RB, et al. Prostatespecific antigen levels after radical prostatectomy 30. 31. 32. 33. 34. 35. 36. 37. in patients with organ-confined and locally extensive prostate cancer. J Urol. 1992;147(3 pt 2): 942-946. Bahnson RR, Dresner SM, Gooding W, Becich MJ. Incidence and prognostic significance of lymphatic and vascular invasion in radical prostatectomy specimens. Prostate. 1989;15:149-155. Salomao DR, Graham SD, Bostwick DG. Microvascular invasion in prostate cancer correlates with pathologic stage. Arch Pathol Lab Med. 1995;119:1050-1054. Schröeder FH. Optimal use of screening. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med. 1996; 335:304-310. DeAntoni EP, Crawford ED, Oesterling JE, et al. Age- and race-specific reference ranges for prostate-specific antigen from a large communitybased study. Urology. 1996;48:234-239. Fowler JE Jr, Bigler SA, Kilambi NK, Land SA. Relationships between prostate-specific antigen and prostate volume in black and white men with benign prostate biopsies. Urology. 1999;53:11751178. Fowler JE Jr, Bigler SA, Miles D, Yalkut DA. Predictors of first repeat biopsy cancer detection with suspected local stage prostate cancer. J Urol. 2000;163:813-818. Fowler JE Jr, Bigler SA. A prospective study of the serum prostate-specific antigen concentrations and Gleason histologic scores of black and white men with prostate carcinoma. Cancer. 1999;86: 836-841. 38. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equal access health care setting. J Urol. 1996;155:1667-1673. 39. Vijayakumar S, Karrison T, Weichselbaum RR, et al. Racial differences in prostate-specific antigen levels in patients with local-regional prostate cancer. Cancer Epidemiol Biomarkers Prev. 1992;1: 541-545. 40. Roach M III, Krall J, Keller JW, et al. The prognostic significance of race and survival from prostate cancer based on patients irradiated on Radiation Therapy Oncology Group protocols (1976-1985). Int J Radiat Oncol Biol Phys. 1992; 24:441-449. 41. Fowler JE Jr, Sanders J, Bigler SA, et al. Percent free prostate-specific antigen and cancer detection in black and white men with total prostate specific antigen 2.5 - 9.9 ng/ml. J Urol. 2000;163:14671470. 42. Fowler J Jr. PSA functions in black and caucasian males. Paper presented at: 10th International Prostate Cancer Update; February 2-6, 2000; Vail, Colo. 43. Partin AW, Yoo J, Carter HB, et al. The use of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol. 1993;150: 110-114. Addendum J Urol. 1994;152:172-173. 44. Partin AW, Kattan MW, Subong ENP, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA. 1997;277:1445-1451. Supplement REVIEWS IN UROLOGY 9