Efficacy of prostatic fossa biopsy in detecting local recurrence after radical prostatectomy

ADULT UROLOGY

EFFICACY OF PROSTATIC FOSSA BIOPSY IN DETECTING LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY YOSHIO NAYA, KOJI OKIHARA, ROBERT B. EVANS,

AND

RICHARD J. BABAIAN

ABSTRACT Objectives. To evaluate retrospectively the efficacy of prostatic fossa biopsy in detecting local recurrence of prostate cancer in men with biochemical failure after radical prostatectomy. Methods. Between January 1997 and December 2002, 100 men without prior adjuvant therapy after radical prostatectomy underwent transrectal ultrasound (TRUS)-guided biopsy of the prostatic fossa. The TRUS findings, digital rectal examination (DRE) findings, serum total prostate-specific antigen (PSA) level at TRUS, PSA velocity, and pathologic stage and Gleason score of the radical prostatectomy specimen were correlated with the biopsy results. Results. Overall, 29 (29%) of the 100 men who underwent biopsy had documented local recurrence. The sensitivity and specificity of DRE to detect biopsy-proven local recurrence was 72.4% and 64.8%, respectively. The corresponding values for TRUS were 86.2% and 53.5%. None of the men with a serum PSA concentration of less than 0.5 ng/mL at biopsy who had normal results for both TRUS and DRE had a biopsy-proven local recurrence. By stepwise multivariate logistic regression analysis, abnormal TRUS findings and serum PSA concentration at biopsy were independent predictors for positive fossa biopsy results. The combination of TRUS and serum PSA concentration was the best predictive model for a positive fossa biopsy result. Conclusions. Prostatic fossa biopsy should be avoided in patients with both or either normal DRE or TRUS findings when the PSA level is less than 0.5 ng/mL. UROLOGY 66: 350–355, 2005. © 2005 Elsevier Inc.

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rostate cancer is the most common nondermatologic cancer and the second most common cause of cancer death among American men.1 Between 25% and 50% of men with clinically localized prostate cancer who undergo radical prostatectomy (RP) with curative intent develop biochemical and/or clinical recurrence within 10 years of RP.2– 4 Classically, treatment failure was defined by either the presence of a palpable fossa abnormality or the development of metastatic disease. Currently, treatment failure is defined as a serum prostate-specific antigen (PSA) level rising from undetectable to detectable.2 It is clinically important to distinguish local recurrence in the pros-

tatic fossa alone from metastatic disease to determine the optimal second-line treatment. Ornstein et al.5 reported that transrectal ultrasound (TRUS)guided prostatic fossa biopsy is frequently recommended for patients who have a detectable serum PSA concentration after RP. Although TRUS is a sensitive tool for detecting local recurrence, it lacks specificity.6 Some investigators6 – 8 reported that 38% to 54% of patients who underwent prostatic fossa biopsy had biopsy-proven local recurrence. We retrospectively reviewed 126 patients who underwent prostatic fossa biopsy at the University of Texas M.D. Anderson Cancer Center. MATERIAL AND METHODS

From the Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas Dr. Naya is currently at Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan. Reprint requests: Richard J. Babaian, M.D., Department of Urology, Unit 446, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail: [email protected] Submitted: November 16, 2004, accepted (with revisions): March 2, 2005 © 2005 ELSEVIER INC. 350

ALL RIGHTS RESERVED

Between January 1997 and December 2002, 130 men underwent TRUS-guided prostate fossa biopsy after RP. Of these 130 patients, 4 had a history of previous anastomotic biopsy and were excluded from analysis. Of the remaining 126 men, 26 had undergone prior adjuvant therapy after RP and were also excluded from the analysis, leaving 100 men. Biochemical failure after RP (PSA 0.1 ng/mL or greater) was observed in 99 men and 1 man had abnormal digital rectal examination (DRE) findings with an undetectable serum PSA level. Of the 99 men with biochemical failure, 45 had an abnormal DRE 0090-4295/05/$30.00 doi:10.1016/j.urology.2005.03.014

finding. Gray-scale TRUS was performed using an 1846 ultrasound scanner with a type 8551 7.0-MHz side-fire biplane probe (B&K, Herlev, Denmark) until July 2002 and a Hawk ultrasound scanner type 2102 XDI with a type 8808 7.5-MHz side-fire biplane probe (B&K) thereafter. TRUS examinations were performed by urologists specifically trained in TRUS of the prostate. The TRUS findings were considered to be suggestive of local prostate cancer recurrence if any hypoechoic lesion was identified at or around the area of anastomosis, at the bladder neck, or in the retrovesical space or if any asymmetry of the anastomosis was noted. The technique of systematic prostatic fossa biopsy was performed by randomly sampling the right and left side of the vesicourethral anastomosis from medial to lateral. Systematic biopsy of the prostatic fossa or a combination of systematic biopsy and directed biopsy to an area corresponding to an abnormal TRUS or DRE finding was performed in 87 men (61 systematic only, 26 combination systematic and directed). The number of biopsy cores taken from these 87 patients varied; 9 underwent two-core biopsy, 3 three-core biopsy, 66 four-core biopsy, and 9 six-core biopsy. Thirteen patients underwent directed biopsy only. Overall, 39 men had biopsy cores taken from visibly or palpably abnormal areas, and 61 patients underwent only systematic or undirected biopsy. The TRUS findings, DRE findings, serum total PSA concentration at fossa biopsy, lowest serum PSA concentration after RP, PSA velocity after RP, pathologic stage, Gleason score of the RP specimen, and time to PSA failure after RP were recorded for each patient. The Mann-Whitney U test and Pearson chi-square test were performed to clarify the difference between men with positive and men with negative biopsy results. Stepwise multivariate logistic regression analysis was performed to determine biopsy-proven independent predictors of local recurrence. All statistical analyses were performed using the Statistical Package for Social Sciences software, version 11.5 (SPSS, Chicago, Ill), with P ⬍0.05 considered statistically significant.

RESULTS Overall, the prostatic fossa biopsy strategy detected a local recurrence in 29 (29.0%) of 100 men. The clinicopathologic features of the 100 patients are shown in Table I. The median serum PSA concentration at TRUS and biopsy was significantly greater in patients who had biopsy-proven local recurrence than in those with negative biopsy results (P ⫽ 0.001). Overall, the sensitivity and specificity of the DRE to detect a biopsy-proven local recurrence was 72.4% and 64.8%, respectively, compared with 86.2% and 53.5%, respectively, for TRUS. Of the 46 patients with an abnormal DRE finding, 21 (45.7%) had positive findings at prostatic fossa biopsy. TRUS showed a lesion suggestive of local recurrence in 58 patients, 25 (43.1%) of whom had a positive prostatic fossa biopsy. Of the 41 patients with both abnormal TRUS and DRE findings, 21 (51.2%) had positive prostatic fossa biopsy results. The likelihood of a positive biopsy in men with both normal DRE and TRUS findings who underwent only undirected biopsies was significantly lower than that for men who underwent directed biopsies (P ⬍0.0001). The PSA velocity after RP in UROLOGY 66 (2), 2005

men with a positive biopsy was greater than that in men with a negative biopsy and showed a trend toward statistical significance (P ⫽ 0.05). No significant differences were found in the likelihood of a positive biopsy among men who underwent undirected prostatic fossa biopsy with various numbers of cores. No significant differences were noted between patients with a positive or a negative biopsy result based on age, PSA nadir after RP (detectable versus undetectable), Gleason score of the RP specimen, pathologic T stage, surgical margin status, seminal vesicle involvement, time from RP to fossa biopsy, time to PSA failure, or postprostatectomy therapy. A greater detection rate of local recurrence was associated with a greater serum PSA concentration at biopsy (P ⫽ 0.002, 5 df [degrees of freedom], Table II). A significant difference was noted in the detection rate of local recurrence between men with a serum PSA concentration less than 0.5 ng/mL (7.7%) and those with a PSA concentration of 0.5 ng/mL or greater (36.5%, P ⫽ 0.0006). Likewise, a significant difference was found in the detection rate of local recurrence between men with serum PSA concentrations of 2 ng/mL or less and those with PSA concentrations greater than 2 ng/mL (P ⫽ 0.0004). Also, a significant difference was found in the detection rate of local recurrence between men with serum PSA concentrations of 3 ng/mL or less and those with PSA concentrations greater than 3 ng/mL (P ⫽ 0.0001). No man with a serum PSA concentration less than 0.5 ng/mL at biopsy and either normal TRUS or DRE findings had biopsy-proven local recurrence. In these patients with a PSA concentration less than 0.5 ng/ mL, the sensitivity and specificity was 100% (2 of 2) and 54.2% (13 of 24) for TRUS and 100% (2 of 2) and 66.7% (16 of 24) for DRE, respectively. In patients with a serum PSA concentration between 0.5 and 1.0 ng/mL, the sensitivity and specificity was 88.9% (8 of 9) and 47.6% (10 of 21) for TRUS and 77.8% (7 of 9) and 61.9% (13 of 21) for DRE, respectively. In patients with a serum PSA concentration between 1.01 and 2.0 ng/mL, the sensitivity and specificity was 40% (2 of 5) and 58.8% (10 of 17) for TRUS and 40% (2 of 5) and 70.6% (12 of 17) for DRE, respectively. In patients with a serum PSA concentration between 2.01 and 3 ng/mL, the sensitivity and specificity was 100% (2 of 2) and 50% (2 of 4) for TRUS and 100% (2 of 2) and 75% (3 of 4) for DRE, respectively. In patients with a serum PSA concentration greater than 3.0 ng/mL, the sensitivity and specificity was 100% (11 of 11) and 60% (3 of 5) for TRUS and 72.7% (8 of 11) and 40% (2 of 5) for DRE, respectively. The results of univariate and stepwise logistic regression analyses to determine independent predictors of prostatic fossa biopsy results are given in 351

TABLE I. Clinicopathologic features Characteristic

Biopsy Positive

Biopsy Negative

P Value

Median age* (yr) Median preoperative PSA* (ng/mL) Median PSA at biopsy* (ng/mL) PSA nadir (%) Detectable (n ⫽ 36) Undetectable (n ⫽ 64) Median PSA velocity after RRP* (ng/ mL/yr) DRE and TRUS (%) Both abnormal TRUS only abnormal DRE only abnormal Both normal Biopsy technique (%) Undirected biopsy only Directed biopsy only Combination of undirected biopsy with directed biopsy No. of cores of undirected biopsy (%) 2 3 4 6 Gleason score of RRP specimen ⱕ6

63.0 (60.6–64.8) 9.0 (6.2–11.8) 2.0 (0–3.4)

65.0 (63.2–66.8) 10.6 (6.7–14.5) 0.7 (0–1.0)

0.874† 0.002† 0.001†

12 (33.3) 17 (26.6)

24 (66.7) 47 (73.4)

0.46 (0–8.60)

0.25 (0–0.70)

21 (51.2) 4 (23.5) 0 (0) 4 (10.8)

20 (48.8) 13 (76.5) 5 (100) 33 (89.2)

8 (13.1) 9 (69.2)

53 (86.9) 4 (30.8)

12 (46.2)

14 (53.8)

0 (0) 1 (50) 4 (8.9) 1 (11.1)

3 (100) 1 (50) 41 (91.1) 8 (88.9) 8 (80)

7 ⱖ8 No information Pathologic T stage pT2

10 (21.7) 8 (29.6) 9 (60)

36 (78.3) 27 (70.4) 6 (40)

14 (33.3)

28 (66.7)

pT3 or T4 No information Surgical margin Positive

10 (19.6) 5 (71.4)

41 (80.4) 2 (28.6)

12 (29.3)

29 (70.7)

13 (24.5) 4 (66.7)

40 (75.5) 2 (33.3)

4 (21.1)

15 (78.9)

Negative No information Median time to biopsy since RRP* (mo) Median time to PSA failure* (mo)

0.05† ⬍0.0001, 3 df‡

⬍0.0001, 2 df‡

2 (20)

Negative No information Seminal vesicle involvement Positive

0.474, 1 df‡

0.411, 3 df‡

0.939, 2 df (excluding information from analysis)‡

0.132, 1 df (excluding no information from analysis)‡

0.606, 1 df (excluding information from analysis)‡

0.540, 1 df (excluding information from analysis)‡

21 (28) 4 (66.7) 45.0 (31.8–58.2)

54 (72) 2 (33.3) 34.0 (26.7–41.3)

0.082†

24.5 (18.7–30.3)

25.0 (18.4–31.6)

0.762†

KEY: PSA ⫽ prostate-specific antigen; RRP ⫽ radical retropubic prostatectomy; DRE ⫽ digital rectal examination; TRUS ⫽ transrectal ultrasonography; df ⫽ degrees of freedom. Data in parentheses are percentages, unless noted otherwise. * Data in parentheses are 95% confidence intervals. † Mann-Whitney U test. ‡ Pearson’s chi-square test.

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TABLE II. Relationship of biopsy result with serum PSA concentration Biopsy Positive Rate (%) PSA Level (ng/mL)

Abnormal DRE Only

Abnormal TRUS Only

Both TRUS and DRE Abnormal

Both TRUS and DRE Normal

Total*

0/2 (0) 0/2 (0) — — 0/1 (0) — 0/5 (0)

0/5 (0) 1/6 (16.7) 0/2 (0) 0/1 (0) 3/3 (100) — 4/17 (23.5)

2/8 (25.0) 7/13 (53.8) 2/7 (28.6) 2/3 (66.7) 3/4 (75.0) 5/6 (83.3) 21/41 (51.2)

0/11 (0) 1/9 (11.1) 3/13 (20.0) 0/2 (0) — 0/2 (0) 4/37 (10.8)

2/26 (7.7) 9/30 (30.0) 5/22 (22.7) 2/6 (33.3) 6/8 (75.0) 5/8 (62.5) 29/100 (29.0)

⬍0.5 0.5–1.0 1.01–2.0 2.01–3.0 3.01–5.0 ⬎5.0 Total

Abbreviations as in Table I. * Pearson chi-square test, PSA ⬍0.5 vs. ⱖ0.5 ng/mL; P ⫽ 0.0006, 1 df for biopsy positive rate; PSA ⱕ2.0 vs. ⬎2.0 ng/mL, P ⫽ 0.0005, 1 df for biopsy positive rate; Pearson chi-square test, PSA ⱕ3.0 vs. ⬎3.0 ng/mL, P ⫽ 0.0001, 1 df for biopsy positive rate.

TABLE III. Stepwise multivariate logistic regression analysis to determine predictability of fossa biopsy Univariate Variable Age TRUS DRE PSA at the time of biopsy (ng/mL) ⬍0.5 0.5–1 1.01–2 2.01–3 ⬎3 PSA velocity after RP (ng/mL/yr) ⬍0.5 0.5–1.49 ⱖ1.5

Multivariate

Chi-Square

P Value

Chi-Square

P Value

0.110 23.120 19.853 18.801 — 0.021 0.539 0.058 14.617 1.068 — 0.002 1.037

0.740 ⬍0.0001 ⬍0.0001 ⬍0.0001 — 0.885 0.463 0.809 ⬍0.0001 0.586 — 0.961 0.309

— 23.120 2.444 13.363 — 0.015 0.005 0.007 9.626 — — — —

— ⬍0.0001 0.118 0.01 — 0.904 0.942 0.934 0.002 — — — —

Abbreviations as in Table I.

Table III. By univariate logistic regression analysis, abnormal TRUS findings (chi-square 13.341, P ⬍0.0001), abnormal DRE findings (chi-square 11.472, P ⫽ 0.001), and abnormal PSA level (chisquare 18.501, P ⫽ 0.001) were significant predictors for a positive result for fossa biopsy. By stepwise multivariate logistic regression analysis, TRUS (chi-square 13.341, P ⬍0.0001) and serum PSA concentration at biopsy (chi-square 13.363, P ⫽ 0.01) were independent predictors for positive fossa biopsy results (Table III). The combination of normal TRUS findings and a serum PSA concentration less than 0.5 ng/mL at prostatic fossa biopsy was the best predictive model for negative fossa biopsy results (chi-square 21.808, P ⬍0.0001) and improved the predictability compared with the use of TRUS alone (P ⬍0.0001). The combination of abnormal DRE findings and PSA level of 3 ng/mL or greater and the combination of abnormal TRUS and DRE findings demonstrated a chi-square statistic of 20.973 (P ⬍0.0001) and 17.027 (P ⬍0.0001), respecUROLOGY 66 (2), 2005

tively, and improved the predictability for a positive fossa biopsy result compared with the use of TRUS alone (P ⬍0.0001). The combination use of TRUS, DRE, and serum PSA concentration of 3 ng/mL or greater demonstrated a chi-square statistic of 17.978 (P ⬍0.0001) and improved the predictability for a positive biopsy result compared with the use of TRUS alone. COMMENT After RP, the serum PSA concentration should reach a nadir at an undetectable level. A detectable and increasing PSA concentration after RP suggests persistent or recurrent prostate cancer. Distinguishing local recurrence from distant metastasis is clinically important in patients with an elevated PSA level to facilitate the choice of second-line therapy. Local recurrence of prostate cancer after RP is associated with a significant risk of disease progression.9 Salvage radiotherapy has the potential to control the progression of local recurrent 353

disease. In selected patients with biochemical failure and pathologically confirmed local recurrence, a greater response rate to radiotherapy has been reported compared with patients without biopsyproven local recurrence.10 The likelihood of biopsy-proven local recurrence after RP has been reported to vary between 38% and 54%.5–7 In our study, 32% of the men who underwent fossa biopsy after RP had positive biopsy results. Our local recurrence detection rate was comparable to that of previous studies. Foster et al.11 reported that the first fossa biopsy revealed local recurrence in 35% of their patients, and repeat fossa biopsies were positive in 47%. Other investigators reported detection rates of 30%7 and 35%6,8 for the initial fossa biopsy. Saleem et al.7 used a six-core biopsy schema, with one core from each side of the bladder neck, one from each side of the anastomosis, and two from the retrovesical region for men with negative TRUS and DRE results. Leventis et al.8 used a fourcore biopsy schema, with one core from each side of the anastomosis, one toward the bladder neck, and one toward the external urethral sphincter for men with negative TRUS and DRE findings. We used four cores, two from each side of the anastomosis for most patients without abnormal TRUS and DRE findings; our procedure was similar to that of Leventis et al.8 The likelihood of biopsyproven local recurrence at the initial biopsy using the four-core strategy was similar to that reported using a six-core strategy. Connolly et al.6 reported that 66% of local recurrent prostate cancer was in the perianastomotic location, with the area of the bladder neck the second most common area of recurrence (16%). On the basis of these data, a fourcore strategy for biopsy of the prostatic fossa may cover approximately 80% of the regions of interest for local recurrence, when TRUS and DRE findings are both normal. Increasing the number of cores did not markedly improve the detection rate of local recurrence. In this study, none of the men with normal DRE and/or TRUS findings and a PSA concentration less than 0.5 ng/mL had biopsy-proven local recurrence (0 of 18, 95% confidence interval 0.00 to 18.53). This result was similar to the findings of Saleem et al.7 These findings support avoiding a fossa biopsy under these circumstances. In the current study, multivariate logistic regression analysis indicated that the combination of TRUS and PSA level was the best model predictive of biopsyproven local recurrence. In this study, prostatic fossa biopsy yielded a 26.9% detection rate in men with a PSA value between 0.5 and 2.0 ng/mL. The detection rate of local recurrence in men with serum PSA concentrations of 0.5 to 2.0 ng/mL was greater than that 354

for men with a serum PSA concentration of less than 0.5 ng/mL, the difference approached statistical significance (P ⫽ 0.0502). In the studies reported by Saleem et al.7 and Leventis et al.,8 prostatic fossa biopsy in men with a total PSA value between 0.5 and 2.0 ng/mL had a cancer detection rate of approximately 30%. Forman et al.12 reported on 47 men who had received radiotherapy because they had detectable PSA concentrations after RP. Of those men with a PSA concentration of 2.0 ng/mL or less, 83% were disease free 3 years after radiotherapy compared with 33% of the men with a PSA concentration greater than 2.0 ng/mL at radiotherapy. In contrast, it should be noted that Koppie et al.13 reported that a positive fossa biopsy result did not predict an improved outcome after radiotherapy following RP. The remaining unanswered questions are whether any given individual has only local recurrence as opposed to concominant metastatic disease and whether the outcome of patients receiving adjuvant radiotherapy after prostatectomy is related to the prostatic fossa biopsy results. CONCLUSIONS TRUS and TRUS-guided prostatic fossa biopsy currently are the most efficient and cost-effective tools for detecting local recurrence of cancer after RP; however, both present limitations in the detection of recurrence. Prostatic fossa biopsies should be avoided in men with normal DRE and/or TRUS findings when the PSA level is less than 0.5 ng/mL because of the low rate of positivity. All other men fall into subgroups with at least an intermediate risk (greater than 10%) risk of a positive fossa biopsy. REFERENCES 1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53: 5–26, 2003. 2. Carroll P: Rising PSA after a radical treatment. Eur Urol 40(suppl 2): 9 –16, 2001. 3. Zincke H, Oesterling JE, Blute ML, et al: Long-term (15 years) results after radical prostatectomy for clinical localized (stage T2 or lower) prostate cancer. J Urol 152: 1850 –1857, 1994. 4. Han M, Partin AW, Pound CR, et al: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy: the 15-year Johns Hopkins experience. Urol Clin North Am 28: 555–565, 2001. 5. Ornstein DK, Colberg JW, Virgo KS, et al: Evaluation and management of men whose radical prostatectomies failed: results of an international survey. Urology 52: 1047–1054, 1998. 6. Connolly JA, Shinohara K, Presti JC Jr, et al: Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins. Urology 47: 225–231, 1996. 7. Saleem MD, Sanders H, Abu El Naser M, et al: Factors predicting cancer detection in biopsy of the prostatic fossa after radical prostatectomy. Urology 51: 283–286, 1998. UROLOGY 66 (2), 2005

8. Leventis AK, Shariat SF, and Slawin KM: Local recurrence after radical prostatectomy: correlation of US features with prostatic fossa biopsy findings. Radiology 219: 432– 439, 2001. 9. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281: 1591–1597, 1999. 10. Rogers R, Grossfeld GD, Roach M III, et al: Radiation therapy for the management of biopsy proved local recurrence after radical prostatectomy. J Urol 160: 1748 –1753, 1998.

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11. Foster LS, Jajodia P, Fournier G Jr, et al: The value of prostatic specific antigen and transrectal ultrasound guided biopsy in detecting prostatic fossa recurrences following radical prostatectomy. J Urol 149: 1024 –1028, 1993. 12. Forman JD, Meetze K, Pontes E, et al: Therapeutic irradiation for patients with an elevated post-prostatectomy prostate specific antigen. J Urol 158: 1436 –1439, 1997. 13. Koppie TM, Grossfeld GD, Nudell DM, et al: Is anastamotic biopsy necessary before radiotherapy after radical prostatectomy? J Urol 166: 111–115, 2001.

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