PREDICTORS OF FIRST REPEAT BIOPSY CANCER DETECTION WITH SUSPECTED LOCAL STAGE PROSTATE CANCER

0022-5347/00/1633-0813/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 163, 813– 818, March 2000 Printed in U.S.A.

PREDICTORS OF FIRST REPEAT BIOPSY CANCER DETECTION WITH SUSPECTED LOCAL STAGE PROSTATE CANCER JACKSON E. FOWLER, JR., STEVEN A. BIGLER, DEREK MILES

AND

DENIS A. YALKUT

From the Division of Urology and Department of Pathology, University of Mississippi School of Medicine and Section of Urology, Veterans Affairs Medical Center, Jackson, Mississippi

ABSTRACT

Purpose: We determine demographic and tumor related predictors of repeat biopsy cancer detection in men with suspected stage T1c-2 prostate cancer. Materials and Methods: The study population included 298 consecutive men with suspected stage T1c-2 prostate cancer who had a benign prostate biopsy at 1 institution between January 1, 1992 and April 1, 1999 and underwent 1 repeat biopsy. Mean age plus or minus standard deviation was 66.8 ⫾ 6.7 years for 133 black (55%) and 165 white (45%) patients. Clinical measures included determination of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, prostate specific antigen (PSA), PSA density, annualized interbiopsy PSA change, percent free PSA (201 cases) and PSA velocity (171). Results: Cancer was detected on repeat biopsy in 80 cases (27%). Significant differences between patients with benign and malignant repeat biopsies included age (p ⫽ 0.001), PSA density (p ⫽ 0.0001), percent free PSA (p ⫽ 0.0001) and PSA velocity (p ⫽ 0.009). High grade prostatic intraepithelial neoplasia in an initial benign biopsy was not predictive of cancer in repeat biopsy (p ⫽ 0.12). Multiple logistic regression analysis of all cases showed that age (p ⫽ 0.002) and PSA density (p ⫽ 0.0002) were independent predictors of cancer. Subset multiple logistic regression analysis modeled with age, PSA density and percent free PSA demonstrated that age (p ⫽ 0.002) and percent free PSA (p ⫽ 0.0001) were significant independent predictors of malignancy. Subset multiple logistic regression analysis modeled with age, PSA density, percent free PSA and PSA velocity revealed that age (p ⫽ 0.02) and percent free PSA (p ⫽ 0.0003) were significant independent predictors of cancer. There were no significant differences between the Gleason scores of cancers detected on repeat biopsy compared to 587 stage T1c-2 cancers detected on initial biopsy during the study period (p ⫽ 0.09). PSA, PSA density, percent free PSA and PSA velocity were not significantly different among men without a cancer diagnosis who had high grade neoplasia in 1 or 2 benign biopsies. Conclusions: Greater than 25% of this population of select patients with suspected stage T1c-2 prostate cancer had malignancy detected on repeat biopsy. Percent free PSA was the most powerful predictor of cancer. High grade prostatic intraepithelial neoplasia was not a predictor of repeat biopsy cancer detection and PSA functions were similar among men without cancer who did and did not have high grade neoplasia in 1 or more benign biopsies. This finding suggests that high grade prostatic intraepithelial neoplasia may not be a reliable indicator of clinically significant existing prostate cancer. KEY WORDS: prostatic neoplasms, prostate, biopsy, prostatic intraepithelial neoplasia, prostate-specific antigen

In contemporary clinical practice greater than 50% of men with suspected stage T1c-2 prostate cancer will have a benign prostate biopsy.1, 2 However, primarily due to an inability to identify and target malignant prostatic tissue with conventional transrectal ultrasonography,3 biopsy sampling errors are inevitable and 1 benign biopsy procedure does not rule out malignancy with a high degree of certainty. Reported experiences indicate that 1 or more repeat prostate biopsies will detect cancer in 16% to 41% of cases with initial benign biopsy.4 –11 A novel investigation has shown that repeat biopsy will identify malignancy in only 77% of cases with previously diagnosed but untreated cancer.12 A variety of clinically available parameters, including prostate specific antigen (PSA),4, 8, 10 PSA density,6, 10, 11 percent

free PSA,5, 6, 13 annualized interbiopsy PSA velocity4, 9, 11 and high grade intraepithelial prostatic neoplasia,7, 9, 14, 15 have been reported to correlate with cancer detection with repeat biopsy procedures. However, the number of patients in these studies has been modest and to our knowledge no study has examined the relative predictive value of all parameters. We examine patient and tumor related characteristics associated with benign and malignant repeat prostate biopsies in men with suspected clinical stage T1c-2 prostate cancer. MATERIALS AND METHODS

Source population. The patients were derived from a series of 1,740 consecutive men with suspected stage T1c-2 cancer due to abnormal digital rectal examination and/or PSA 4.0 ng./ml. or greater who underwent prostate biopsy at the Veterans Affairs Medical Center between January 1, 1992 and April 1, 1999. Of the patients 587 (34%) had a malignant and 1,153 (66%) had a benign biopsy. Repeat biopsy was

Accepted for publication October 15, 1999. Supported by Hybritech, Inc. Any opinions expressed herein are those of the authors and do not necessarily represent opinions or policies of the Department of Veterans Affairs. 813

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REPEAT PROSTATE BIOPSIES

generally recommended when PSA was greater than the age adjusted reference range established by Oesterling et al16 at initial biopsy, increased to a level above that range after initial biopsy or was within that range but palpable abnormalities of the prostate were considered highly suspicious for carcinoma. Repeat biopsy was performed in 298 men (26%) with a benign biopsy. PSA was above the age adjusted reference range in 199 men (67%), PSA had increased to a level above that range in 30 (10%) and the prostate was highly suspicious for carcinoma in 69 (23%). Repeat biopsy was not recommended in 497 of the remaining 855 cases (58%) because PSA was within and had not increased above the age adjusted reference range. PSA was above or increased above that range in 358 cases but repeat biopsy was not performed. Of these patients 135 (16%) had a normal digital rectal examination and underwent transurethral resection of the prostate or open prostatectomy for treatment of bothersome obstructive voiding symptoms after initial biopsy. Repeat biopsy was recommended but refused by 23 patients (3%), was not recommended because of significant co-morbid disease in 10 (1%), is pending in 113 (13%) and was not done in 77 (9%) who died or were lost to followup. Clinical measurements. Data for all patients who underwent repeat biopsy included age and race, presumptive clinical disease stage, biopsy technique, presence or absence of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, PSA, PSA density and annualized interbiopsy PSA change. Percent free PSA was determined at the time of repeat biopsy in 201 cases and PSA velocity was evaluable in 171. Clinical staging of disease was based on digital rectal examination. Men with asymmetry, induration or nodularity of the prostate were presumed to have stage T2 cancer and those without abnormal findings but PSA 4.0 ng./ml. or greater were presumed to have stage T1c cancer.17 Prostate biopsies were performed transrectally with an 18 gauge needle with ultrasound guidance. Between January 1992 and June 1995 peripheral zone biopsy was done using conventional sextant techniques,3 between July 1995 and October 1997 single core bilateral transition zone biopsies were performed with sextant peripheral zone biopsies,18 and since November 1997 peripheral zone biopsy has been done using the 5 region technique described by Eskew et al.19 Regardless of biopsy technique, targeted biopsies of hypoechoic or palpably abnormal areas of the prostate were not done. Cancer was detected in transition zone biopsy specimens in only 2 of 96 cases (2%) and high grade neoplasia was never detected in a transition zone in the absence of coexisting neoplasia in a peripheral zone biopsy. For data analysis patients were considered to have had sextant or 5 region biopsies only. All biopsy specimens were evaluated by a referee genitourinary pathologist (S. A. B.) who was blinded to case status. The Gleason system was used to grade malignant biopsies and benign biopsies were examined for high grade neoplasia.20 Infiltration of prostatic tissue by inflammatory cells was not quantitated. The diagnosis of high grade prostatic intraepithelial neoplasia (formerly prostatic intraepithelial neoplasia 2 and 3) was established using the criteria of Bostwick and Brawer.21 High grade neoplasia cases were characterized by glands and ducts with epithelial cell crowding and stratification, nuclear enlargement with some nuclear size and shape variation, increased chromatin density and clumping, and occasional to frequent large prominent nucleoli. Immunohistochemistry was not routinely used to identify basal cells in these cases. All blood specimens were drawn in an ambulatory setting before prostatic manipulation or biopsy. Total PSA was measured with a monoclonal radioimmunoassay. Free PSA was quantitated with a dual monoclonal radioimmunoassay in 201 patients who underwent repeat prostate biopsy after

August 1996, when the test became available at our institution for clinical research. In these cases 1 portion of the sera was frozen at ⫺70C and assayed for total PSA within 1 to 2 days after the blood draw, and another was frozen at ⫺70C and assayed for free PSA within 1 to 4 weeks. Percent free PSA was calculated as the ratio of free-to-total PSA times 100. The reported total and percent free PSA values refer to those measured before repeat biopsy. Prostate volume was estimated with transrectal ultrasonography immediately before prostate biopsy. Anteroposterior, transverse and longitudinal dimensions of the gland were measured, and volume was calculated using the prolate ellipsoid formula.22 PSA density was calculated by dividing total PSA by prostate volume. The reported PSA density value is that determined before repeat biopsy. Annualized interbiopsy PSA changes were determined by subtracting PSA at repeat biopsy from that at initial biopsy, dividing the results by the biopsy interval in months and multiplying by 12. PSA velocity was determined in 171 men who had 3 or more PSA determinations during an interval of 36 months or greater using the methods described by Carter et al.23 PSA obtained within 3 months after prostate biopsy was excluded from PSA velocity determination because biopsy can produce transient elevation of serum PSA.24 Median time between first and last PSA measurements was 51 months (range 36 to 85) and median number of PSA determinations used to calculate PSA velocities was 4 (range 3 to 7). Statistical analyses. Statistical analyses were performed using computer software. Student’s t test was used to compare continuous variables and Fisher’s exact test was used to compare categorical variables. The significance of relationships between various parameters was assessed with the Pearson correlation. PSA, percent free PSA and PSA density are not normally distributed, and so these parameters were transformed to log 10 in comparative analyses of continuous variables. Statistically significant predictors of cancer detection in univariate analyses were included in logistic regression analyses as continuous variables to identify those with the most significant independent predictive value. The performance of percent free PSA for repeat biopsy cancer detection was assessed with receiver operating characteristics (ROC) curves. All statistical tests were 2-tailed with p ⬍0.05 considered statistically significant. Mean values are reported with standard deviations and, unless otherwise indicated, median values are reported with 25th and 75th quartiles. RESULTS

Cancer was detected on repeat biopsy in 80 of 298 cases (27%). Demographic and tumor related characteristics of all patients and stratified by repeat biopsy results (benign or malignant) are shown in table 1. Patient age, PSA density, percent free PSA and PSA velocity were significantly different for patients with benign and malignant repeat biopsies. There was indirect correlation between age and percent free PSA (p ⫽ 0.003), direct correlation between age and PSA velocity (p ⫽ 0.01), direct correlation between PSA density and PSA velocity (p ⫽ 0.01), indirect correlation between PSA density and percent free PSA (p ⬍0.0001), and indirect correlation between percent free PSA and PSA velocity (p ⫽ 0.03). Logistic regression analyses revealed statistically significant predictors of repeat biopsy cancer detection. In the entire patient group age (p ⫽ 0.002) and PSA density (p ⫽ 0.0002) were significant independent predictors of cancer. Subset analysis of 201 patients with percent free PSA values demonstrated that age (p ⫽ 0.002) and percent free PSA (p ⫽ 0.0001) but not PSA density (p ⫽ 0.28) were significant independent predictors of malignancy. Finally, subset analysis of 118 patients with percent free PSA determinations and evaluable PSA velocities showed that age

815

REPEAT PROSTATE BIOPSIES TABLE 1. Characteristics of all patients and stratified by repeat biopsy results Repeat Biopsy Results All Pts.

p Value* Benign

Malignant

Total No. pts. (%) 298 218 (73) Mean age ⫾ SD 66.8 ⫾ 6.7 65.9 ⫾ 6.7 No. black men (%) 133 (45) 91 (68) No. white men (%) 165 (55) 127 (77) No. digital rectal examination (%): Normal 126 (42) 92 (42) Abnormal 172 (58) 126 (58) Median mos. biopsy interval (25th–75th quartile) 16 (10–25) 15 (9–25) No. indications for repeat biopsy (%): PSA greater than age adjusted reference range 199 (67) 148 (68) Development of PSA greater than age adjusted ref30 (10) 15 (7) erence range Physician concern 69 (23) 55 (25) No. biopsy technique (%): Sextant only 203 (68) 149 (68) Sextant ⫹ 5 region 78 (26) 54 (25) 5 Region only 17 (6) 15 (7) Median ng./ml. PSA (25th–75th quartile) 6.1 (4.4–9.5) 6.0 (4.3–9.6) Median ng./ml./ml. PSA density (25th–75th quartile) 0.13 (0.09–0.20) 0.13 (0.08–0.18) Median % free PSA (25th–75th quartile)† 20 (15–28) 22 (17–29) Median ng./ml./yr. annualized interbiopsy PSA 0.4 (⫺0.01–1.2) 0.3 (⫺0.2–1.0) change (25th–75th quartile) Median ng./ml./yr. PSA velocity (25th–75th quartile)‡ 0.42 (0.02–1.10) 0.24 (⫺0.02–0.85) * Benign versus malignant repeat biopsy. † Determined in 201 patients, including 157 with benign and 44 with malignant biopsies. ‡ Determined in 171 patients, including 129 with benign and 42 with malignant biopsies.

(p ⫽ 0.02) and percent free PSA (p ⫽ 0.0003) but not PSA density (p ⫽ 0.65) or PSA velocity (p ⫽ 0.94) were significant independent predictors of cancer. There were no significant racial differences in repeat biopsy cancer detection but the mean age of black patients (67.8 ⫾ 9.2 years) was significantly greater than that of white patients (66.0 ⫾ 6.3, p ⫽ 0.02). There were no significant racial differences in PSA, PSA density, percent free PSA or PSA velocity. When controlled for age repeat biopsy cancer detection was similar in black and white men (p ⫽ 0.25). Since age influences repeat biopsy cancer detection and men younger than 70 years are most likely to benefit from early stage cancer diagnosis, logistic regression analyses were also modeled with PSA density and percent free PSA for 118 patients younger than 70, and with PSA density, percent free PSA and PSA velocity for 68 younger than 70. In both analyses percent free PSA was the only significant independent predictor of cancer (p ⫽ 0.006 and 0.004, respectively). The area under the ROC curve for percent free PSA was 0.75. Table 2 shows the sensitivity and specificity of percent free PSA for repeat biopsy cancer detection. Table 3 shows relationships between the presence and absence of high grade prostatic intraepithelial neoplasia in the initial biopsy and histology of the repeat biopsy. Repeat biopsy revealed malignancy in 36% of men with and 25% without neoplasia in the initial biopsy (p ⫽ 0.12). The data also demonstrate substantial discordance between the identification of neoplasia on sequential biopsies from an individual patient. Of 48 patients without identifiable cancer who had neoplasia in 1 or 2 biopsy specimens only 10 (21%) had neoplasia in both.

TABLE 2. Sensitivity and specificity of percent free PSA for repeat biopsy cancer detection Percent Free PSA

% Sensitivity

% Specificity

40 35 30 25 20 15 10 5

98.1 98.1 94.3 81.1 67.9 56.6 28.3 3.8

8.1 15.5 23.6 37.2 62.2 83.1 97.3 100.0

80

(27) 68.6 ⫾ 6.5 42 (32) 38 (23)

— 0.001 0.11

34 46 17

(42) (58) (10–28)

1.00

51 15

(64) (19)

14

(18)

0.18 0.01

54 (68) 24 (30) 2 (2) 6.5 (4.7–9.4) 0.15 (0.11–0.26) 14 (9–22) 1.0 (0.0–1.8)

0.23 0.28 0.0001 ⬍0.0001 0.41

0.79 (0.20–1.4)

0.009

TABLE 3. Histology of repeat biopsies stratified by presence or absence of high grade prostatic intraepithelial neoplasia in first biopsy No. First Biopsy (%) Repeat Biopsy Ca Neoplasia present Neoplasia absent Totals

Total No. Neoplasia Present

Neoplasia Absent

18 (36) 10 (20) 22 (44) 50

52 (25) 16 (6) 170 (89) 248

80 26 192 198

Since our study does not confirm other findings that high grade prostatic intraepithelial neoplasia is a significant predictor of cancer on repeat prostate biopsies,7, 9, 14, 15 we explored the characteristics of men without detectable cancer who did not have neoplasia in either biopsy or who had it in 1 or 2 biopsies. There were no significant differences in the variables in the 2 patient groups although there was a trend for a higher prevalence of neoplasia in black men compared to white men (table 4). Gleason scores of cancers diagnosed on repeat biopsy are shown in table 5. Also shown are Gleason scores of 587 consecutive stage T1c-2 cancers diagnosed on an initial biopsy during the study period. The incremental Gleason scores of cancers detected on 1 biopsy or repeat biopsy were not significantly different (p ⫽ 0.09), although there was a trend for higher scores among patients diagnosed on 1 biopsy. DISCUSSION

Our results provide insight into the clinical usefulness of purported predictors of cancer detection on repeat prostate biopsy. Percent free PSA, which helps discriminate between men with PSA 2.5 to 9.9 ng./ml. who are at high and low risk for prostate cancer,25, 26 was the most powerful predictor of repeat biopsy cancer detection. Median percent free PSA of men who did and did not have cancer detected on repeat biopsy was 14 and 22, respectively. Others have also demonstrated significant differences between percent free PSA among men with benign and malignant repeat biopsies, although the levels in patient groups have been variable. For example, Morgan et al reported median percent free PSA of 7

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REPEAT PROSTATE BIOPSIES TABLE 4. Characteristics of 218 patients without cancer based on high grade prostatic intraepithelial neoplasia in the initial or repeat biopsy

No. pts. (%) Mean age ⫾ SD No. black men (%) No. white men (%) No. digital rectal examination (%): Normal Abnormal Median ng./ml. PSA (25th–75th percentile) Median ng./ml./ml. PSA density (25th–75th percentile) Median % free PSA (25th–75th percentile) Median ng./ml./yr. PSA velocity

Neoplasia Absent

Neoplasia Present

170

(78)

48

(71) (83)

26 22

65 105

75 (82) 95 (75) 6.0 (4.1–9.3) 0.13 (0.08–0.18) 22 (16–29) 0.24 (0.00–0.92)

TABLE 5. Gleason score of repeat and initial malignant biopsies with stage T1c-2 cancer Gleason Score

No. Repeat Biopsy (%)

2–4 5–6 7 8–10

15 (19) 38 (48) 21 (26) 6 (8)

65.7 ⫾ 6.7

No. Initial Biopsy (%)* 67 (11)† 272 (46) 147 (25) 101 (17)

Totals 80 587 * Gleason score of stage T1c-2 cancers diagnosed on 1 biopsy during the study period. † Initial versus repeat biopsies p ⫽ 0.09.

and 18 in 67 men with and without detectable cancer, respectively,5 Catalona et al reported mean levels of 16 and 20 in 99 men with and without detectable cancer,6 and Letran et al noted median levels of 15 and 19 in 51, respectively.13 Variability in selection criteria for repeat biopsy or in parameters that impact percent free PSA, such as total PSA, prostate volume and patient age,25 may contribute to these differences. An institutional experience suggests that the performance of percent free PSA for initial and repeat biopsy cancer detection is similar. We determined percent free PSA in 568 consecutive men with suspected stage T1c-2 cancer who had undergone 1 biopsy only since August 1996. Median percent free PSA (25th, 75th quartile) was 12 (8, 19) in men with malignant and 22 (16, 32) in those with benign biopsies. ROC analysis for percent free PSA revealed an area under the curve of 0.79 and a percent free PSA of 30 yielded 95% sensitivity and 30% specificity. These values parallel those for percent free PSA in our repeat biopsy cases. However, the clinical relevance of percent free PSA values may differ in men who have or have not undergone previous biopsy. Specifically, the natural history of most local stage prostate cancers is protracted and, depending on the clinical situation, sensitivity may be less important than specificity when determining cutoffs for repeat biopsy. This consideration is underscored by our observation that repeat biopsy cancer detection is directly related to age and by the probability that a delay in local stage cancer diagnosis may be of less importance in older men than in younger men. All biopsies were reviewed in a blinded manner by an experienced uropathologist who has participated in other studies of high grade prostatic intraepithelial neoplasia and cancer risk.27 However, neoplasia in an initial biopsy was not a significant predictor of cancer in a repeat biopsy in our cases. This finding conflicts with others which indicate that the likelihood of cancer detection with repeat biopsy ranges from 50% to 100% when high grade neoplasia is found on an initial biopsy and 15% to 40% when neoplasia is not identified initially.7, 9, 14, 15 Our large number of patients, which enabled the issue to be approached with more statistical power, is a possible explanation for these divergent observations. It is also noteworthy that the prevalence of high grade

67.1 ⫾ 6.7

(22) (29) (17)

17 (18) 31 (25) 6.5 (4.6–10.7) 0.13 (0.09–0.16) 23 (19–27) 0.23 (⫺0.03–0.70)

p Value — 0.21 0.07 0.32 0.20 0.96 0.69 0.23

neoplasia in our initial biopsy specimens was 17%, which is greater than the 5.5% to 8.3% prevalence in unselected cases that has been reported by others.28, 29 This difference probably reflects the fact that our patients were considered to be at high risk for carcinoma because the prevalence of high grade prostatic intraepithelial neoplasia in all benign biopsies at our institution is only 10%.30 The biracial nature of our population is also contributory since 13% of the white and 21% of the black men had neoplasia in the initial biopsy. Regardless, the observations that PSA density, percent free PSA and PSA velocity were not significantly different among men without detectable cancer who had neoplasia in 1 or 2 biopsies compared to those who had no identifiable neoplasia in any biopsy, and the remarkable discordance in identification of neoplasia in sequential biopsies from individual patients suggest that high grade prostatic intraepithelial neoplasia may not be a useful clinical indicator of existing, clinically significant malignancy. Annualized interbiopsy PSA changes were higher in our patients with a malignant repeat biopsy than in those with a benign repeat biopsy but values were variable in both patient groups and the difference was not statistically significant. This finding is not unexpected because there is substantial physiological variability in PSA31 and the intervals between biopsy procedures were often short. On the other hand, in 171 cases longitudinal PSA measurements during 36 months or longer permitted meaningful calculation of PSA velocities and this parameter was significantly greater in men with than in those without detectable cancer. However, it should be noted that PSA velocity determinations were derived in part from PSA obtained after the last biopsy and the data were not available in all patients at that time. For this reason and because percent free PSA appears to be a better predictor of cancer the current role of PSA velocity for assessing the advisability of repeat biopsy procedures is uncertain. Several other findings in this study merit comment. Unlike some reported experiences with repeat biopsies,4, 8, 10 we found no difference in median PSA of men with benign and malignant repeat biopsies. However, all of our patients had suspected stage T1c-2 cancer and variability of PSA was minimal. PSA density proved to be significantly different among men with benign and malignant repeat biopsies, and was a significant independent predictor of cancer when controlled for age. Due possibly to variability in PSA and in the methods for determining prostate volume, studies of PSA density as a predictor of cancer in repeat biopsies have yielded conflicting results.6, 8, 10, 11 However, given the superiority of percent free PSA compared to PSA density as a predictor of repeat biopsy cancer detection, uncertainty about the role of the latter as a selection parameter for repeat biopsy may be of historical interest only. Median PSA velocity in our cancer patients (0.79 ng./ml. per year) parallels that determined by Carter et al (0.75) by assay of archival serum specimens from men who eventually had prostate cancer.32 This confirmatory observation is important because PSA elevation was the motivating factor for

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REPEAT PROSTATE BIOPSIES

prostate biopsy in many of our patients, whereas those studied by Carter et al were diagnosed before the PSA blood test was available in clinical practice. Median PSA velocity for our patients without detectable cancer (0.25 ng./ml. per year) was greater than that reported for their patients without clinical evidence of carcinoma (0.08).23 Several considerations may account for this difference. Our principal criterion for repeat biopsy was PSA greater than the age adjusted reference range, whereas the majority of men without clinical evidence of carcinoma have PSA less than 2.0 ng./ml., and it is reasonable to believe that PSA velocity of those with low PSA is less than that of those with abnormal PSA elevation. In addition, we addressed the results of a single repeat biopsy but malignancy will be identified with a second or third repeat biopsy in about 8% of cases.4 Therefore, it is probable that some of our patients who had a benign repeat biopsy had undetected carcinoma. We found no racial differences in the crude or age adjusted risk of repeat biopsy cancer detection although high grade neoplasia was more common in the benign biopsies of black men compared to white men who did not have detectable carcinoma.30 The latter finding is consistent with the results of a previously reported cross-sectional study of benign biopsies at our institution which showed that the prevalence of neoplasia was 13% in black and 8% in white men, and with the autopsy study of Sakr which showed that the age stratified prevalence of neoplasia was greater in black men than in white men.33 These observations are important because high grade prostatic intraepithelial neoplasia may be a precursor of prostate cancer, which is more common in black men.34 Finally, the Gleason score of repeat malignant biopsies was not significantly different from those of stage T1c-2 cancers diagnosed on an initial biopsy during the study period. Only 16 of the 80 repeat biopsy cases with carcinoma (20%) have been treated with surgery, and meaningful comparisons of tumor volume and pathological stage in the 2 patient groups are not possible. However, given established relationships between Gleason score and disease-free survival in men with untreated35 and treated36, 37 local stage prostate cancer, the findings suggest that there is no material difference in the risk of identifying tumors with minimal malignant potential when cancer is detected on an initial or repeat biopsy. This information should be useful to the clinician when counseling men about the advantages and disadvantages of repeat biopsies. Limitations of our data are related primarily to the clinical nature of the study. Repeat biopsy was done in only 229 of 587 cases that met our PSA driven indications for the procedure and 69 of 566 that did not meet these criteria. Patients with PSA 4.0 ng./ml. or greater who underwent therapeutic transurethral prostatic resection or open prostatectomy also did not undergo repeat biopsy. This protocol may have biased the results in terms of repeat biopsy cancer detection since in these cases PSA elevation was probably due to prostatic enlargement rather than prostate cancer.38 Although we now perform repeat biopsies 6 to 12 months after an initial benign biopsy, biopsy intervals in our study patients were not uniform. Finally, our selection criteria for repeat biopsy, which emphasize PSA above the age adjusted reference ranges established by Oesterling et al,16 do not necessarily parallel those of others and our results may not be generalizable. CONCLUSIONS

Our study suggests that percent free PSA is the most powerful predictor of repeat biopsy cancer detection in select patients with suspected local stage prostate cancer. Conversely, our results indicate that isolated high grade prostatic intraepithelial neoplasia is not predictive of repeat biopsy cancer detection and PSA functions are similar in men

without detectable cancer who do and do not have neoplasia in 1 or more benign biopsies. The latter observations raise concern about the commonly accepted notion that high grade prostatic intraepithelial neoplasia is an indicator of existing but undetected clinically significant prostate cancer.

REFERENCES

1. Catalona, W. J., Smith, D. S., Ratliff, T. L. et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med, 324: 1156, 1991 2. Rommel, F. M., Agusta, V. E., Breslin, J. A. et al: The use of prostate specific antigen and prostate specific antigen density in the diagnosis of prostate cancer in a community based urology practice. J Urol, 151: 88, 1994 3. Hodge, K. K., McNeal, J. E., Terris, M. K. et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol, 142: 71, 1989 4. Keetch, D. W., Catalona, W. J. and Smith, D. S.: Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol, 151: 1571, 1994 5. Morgan, T. O., McLeod, D. G., Leifer, E. S. et al: Prospective use of free prostate-specific antigen to avoid repeat prostate biopsies in men with elevated total prostate-specific antigen. Urology, 48: 76, 1996 6. Catalona, W. J., Beiser, J. A. and Smith, D. S.: Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol, 158: 2162, 1997 7. Ellis, W. J. and Brawer, M. K.: Repeat prostate needle biopsy: who needs it? J Urol, 153: 1496, 1995 8. Fleshner, N. E., O’Sullivan, M. and Fair, W. R.: Prevalence and predictors of a positive repeat transrectal ultrasound guided needle biopsy of the prostate. J Urol, 158: 505, 1997 9. Perachino, M., di Ciolo, L., Barbetti, V. et al: Results of rebiopsy for suspected prostate cancer in symptomatic men with elevated PSA levels. Eur Urol, 32: 155, 1997 10. Ukimura, O., Durrani, O. and Babaian, R. J.: Role of PSA and its indices in determining the need for repeat prostate biopsies. Urology, 50: 66, 1997 11. Keetch, D. W., McMurtry, J. M., Smith, D. S. et al: Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol, 156: 428, 1996 12. Rabbani, F., Stroumbakis, N., Kava, B. R. et al: Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol, 159: 1247, 1998 13. Letran, J. L., Blase, A. B., Loberiza, F. R. et al: Repeat ultrasound guided prostate needle biopsy: use of free-to-total prostate specific antigen ratio in predicting prostatic carcinoma. J Urol, 160: 426, 1998 14. Raviv, G., Zlotta, A. R., Janssen, Th. et al: Do prostate specific antigen and prostate specific antigen density enhance the detection of prostate carcinoma after initial diagnosis of prostatic intraepithelial neoplasia without concurrent carcinoma? Cancer, 77: 2103, 1996 15. Shepherd, D., Keetch, D. W., Humphrey, P. A. et al: Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostate needle biopsy. J Urol, 156: 460, 1996 16. Oesterling, J. E., Jacobsen, S. J., Chute, C. G. et al.: Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific references ranges. JAMA, 270: 860, 1993 17. Beahrs, O. H., Henson, D., Hutter, R. V. P. et al: Manual for Staging of Cancer, 4th ed. Philadelphia: J. B. Lippincott, 1992 18. Terris, M. K., Pham, T. Q., Issa, M. M. et al: Routine transition zone and seminal vesicle biopsies in all patients undergoing transrectal ultrasound guided prostate biopsies are not indicated. J Urol, 157: 204, 1997 19. Eskew, L. A., Bare, R. L. and McCullough, D. L.: Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol, 157: 199, 1997 20. Gleason, D. F.: Classification of prostatic carcinomas. Cancer Chemother Rep, 50: 125, 1966 21. Bostwick, D. G. and Brawer, M. K.: Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer, 59: 788, 1987

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REPEAT PROSTATE BIOPSIES

22. Terris, M. K. and Stamey, T. A.: Determination of prostate volume by transrectal ultrasound. J Urol, 145: 984, 1991 23. Carter, H. B., Pearson, J. D., Waclawiw, Z. et al: Prostatespecific antigen variability in men without prostate cancer: Effect of sampling interval on prostate-specific antigen velocity. Urology, 45: 591, 1995 24. Yuan, J. J. J., Coplen, D. E., Petros, J. A. et al: Effects of rectal examination, prostatic massage, ultrasonography and needle biopsy on serum prostate specific antigen levels. J Urol, 147: 810, 1992 25. Catalona, W. J., Partin, A. W., Slawin, K. M. et al: Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA, 279: 1542, 1998 26. Catalona, W. J., Smith, D. S. and Ornstein, D. K.: Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA, 277: 1452, 1997 27. Brawer, M. K., Bigler, S. A., Sohlberg, O. E. et al: Significance of prostatic intraepithelial neoplasia on prostate needle biopsy. Urology, 38: 103, 1991 28. Bostwick, D. G., Qian, J. and Frankel, K.: The incidence of high grade prostatic intraepithelial neoplasia in needle biopsies. J Urol, 154: 1791, 1995 29. Wills, M. L., Hamper, U. M., Partin, A. W. et al: Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens. Urology, 49: 367, 1997 30. Bigler, S. A., Fowler, J. E., Jr., Land, S. A. et al: High grade

31.

32.

33.

34.

35.

36.

37.

38.

prostatic intraepithelial neoplasia (PIN) in Caucasians and African Americans. Lab Invest, 79: 90A, 1999 Prestigiacomo, A. F. and Stamey, T. A.: Physiological variation of serum prostate specific antigen in the 4.0 to 10.0 ng/ml range in male volunteers. J Urol, 155: 1977, 1996 Carter, H. B., Pearson, J. D., Metter, E. J. et al.: Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. JAMA, 267: 2215, 1992 Sakr, W. A.: Prostatic intraepithelial neoplasia: a marker for high-risk groups and a potential target for chemoprevention. Eur Urol, 35: 474, 1999 Miller, B. A., Ries, L. A. G., Hankey, B. F. et al: SEER Cancer Statistics Review. 1973–1990. Bethesda, Maryland: National Cancer Institute. NIH Pub. No., 93–2789, 1993 Albertsen, P. C., Hanley, J. A., Gleason, D. F. et al: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA, 280: 975, 1998 Pound, C. R., Partin, A. W., Epstein, J. I. et al: Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am, 24: 395, 1997 Zagars, G. K., Pollack, A. and von Eschenbach, A. C.: Prognostic factors for clinically localized prostate carcinoma: analysis of 938 patients irradiated in the prostate specific antigen era. Cancer, 79: 1370, 1997 Fowler, J. E., Jr., Bigler, S. A. and Kolski, J. M.: Prostate cancer detection in candidates for open prostatectomy. J Urol, 160: 2107, 1998