- Email: [email protected]
Office Based Transrectal Saturation Biopsy Improves Prostate Cancer Detection Compared to Extended Biopsy in the Repeat Biopsy Population
Office Based Transrectal Saturation Biopsy Improves Prostate Cancer Detection Compared to Extended Biopsy in the Repeat Biopsy Population Osama M. Zaytoun, Ayman S. Moussa, Tianming Gao, Khaled Fareed and J. Stephen Jones*,† From the Glickman Urological and Kidney Institute and Department of Quantitative Health Sciences (TG), Cleveland Clinic, Cleveland, Ohio
Abbreviations and Acronyms ASAP ⫽ atypical small acinar proliferation DRE ⫽ digital rectal examination HGPIN ⫽ high grade prostatic intraepithelial neoplasia PBx ⫽ prostate biopsy PCa ⫽ prostate cancer PSA ⫽ prostate specific antigen TRUS ⫽ transrectal ultrasound Submitted for publication January 13, 2011. Study received institutional review board approval. * Correspondence: Department of Regional Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave., A100, Cleveland Ohio 44195 (telephone: 216-444-2470; FAX: 216-445-2267; e-mail: [email protected]). † Financial interest and/or other relationship with Pfizer, Cook, Abbott, Endocare and GTx.
For another article on a related topic see page 1093.
Purpose: Multiple studies have shown significant prostate cancer detection for repeat biopsy. However, the best approach regarding core number and location remains controversial. Transrectal saturation biopsy is believed to increase cancer detection but to our knowledge no studies comparing it to 12 to 14-core extended biopsy have been published. We compared saturation and extended repeat biopsy protocols after initially negative biopsy. Materials and Methods: A total of 1,056 men underwent prostate biopsy after initially negative biopsy. The extended biopsy group included 393 men with 12 to 14-core repeat biopsy. The saturation biopsy group included 663 men with 20 to 24-core repeat biopsy. We analyzed demographics and prostate cancer between the 2 groups. We compared prostate cancer detection in patients with previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia as well as the risk of detecting clinically insignificant tumors. Results: Prostate cancer was detected in 315 of the 1,056 patients (29.8%). Saturation biopsy detected almost a third more cancers (32.7% vs 24.9%, p ⫽ 0.0075). In patients with a benign initial biopsy saturation biopsy achieved significantly greater prostate cancer detection (33.3% vs 25.6%, p ⫽ 0.027). For previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia there was a trend toward higher prostate cancer detection rate in the saturation group but it did not attain statistical significance (31.2% vs 23.3%, p ⫽ 0.13). Of 315 positive biopsies 119 (37.8%) revealed clinically insignificant cancer (40.1% vs 32.6%, p ⫽ 0.2). Conclusions: Compared to extended biopsy, office based saturation biopsy significantly increases cancer detection on repeat biopsy. The potential for increased detection of clinically insignificant cancer should be weighed against missing significant cases. Key Words: prostate, prostatic neoplasms, biopsy, physicians’ offices, reoperation
850
www.jurology.com
AFTER its introduction by Hodge et al1 sextant PBx remained the mainstay of PCa diagnosis for several years. However, several investigators reported a high probability that this limited parasagittal scheme would miss cancer.2,3 Currently initial PBx should include at least 10 to 14 ex-
tended cores, including the lateral and anterior prostate zones, based on superior cancer detection rates.4,5 Even with the widespread application of extended PBx it is well recognized that many PCa cases are still missed at initial PBx due to sampling error and, thus, negative PBx does
0022-5347/11/1863-0850/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 850-854, September 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.04.069
AND
RESEARCH, INC.
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
not exclude cancer.6 A challenging dilemma facing urologists is the treatment of patients with initially negative PBx but in whom there remains suspicion for PCa. This suspicion is usually based on clinical and/or pathological indicators, ie DRE, increased PSA or previous biopsy showing ASAP and/or HGPIN. Studies describe a significant cancer detection rate of repeat biopsy in those populations.2,7 However, to our knowledge the best approach to repeat PBx remains undefined. Of all repeat biopsies that patients may undergo the initial repeat PBx (second overall biopsy) is characterized by the highest PCa detection7,8 The concept of increasing the number of cores has led to the emergence of transrectal saturation PBx, in which 20 or more cores are obtained in systematic fashion.9 Although we reported that saturation PBx does not improve cancer detection as an initial biopsy strategy,10 our series and several others11–14 suggested that saturation PBx enhances cancer detection in a repeat PBx population. With improvement in periprostatic block, concern about the morbidity of saturation biopsy appears unfounded. The safety and efficacy of saturation PBx are well established in many series while counterintuitively the complication rate is not higher than that of extended PBx.15,16 Also, saturation PBx can be safely and effectively done in the office using local anesthesia.17 Although it has been assumed that saturation PBx ensures a superior PCa detection rate at repeat biopsy, data comparing its cancer detection rate to that of extended repeat biopsy are lacking. We compared the results of extended and saturation PBx protocols in a first repeat PBx population.
patients received hormonal manipulation between the 2 biopsies. During the study period we recommended routine delayed interval biopsy 2 to 3 years after initial biopsy in men with HGPIN based on studies showing significant cancer detection at these intervals. In patients with initially detected ASAP we recommended repeat biopsy 6 month after the first PBx. In patients with initially benign biopsy findings the time of repeat biopsy was tailored by the risk indicators in each individual.
PBx and Patient Grouping The attending urologist practice pattern was the major factor determining the decision to perform repeat biopsy as well as the sample number and site. All TRUS guided biopsies were performed in an office setting with periprostatic block used routinely since 2002.17 The 12 to 14-core template obtained medial and lateral cores on each side from the base, mid gland and apex while in a few patients an additional core was obtained on each side of the extreme apex. Most clinicians used an extended template of 12 or 14 cores consistently during the study period and others used saturation biopsy for repeat biopsy. Patients were divided into 2 groups, including 393 with a 12 to 14-core biopsy scheme (extended PBx group) and 663 with a 20 to 24-core biopsy scheme (saturation PBx group). Based on early initial success several of our urologists began to perform 24-core saturation PBx in 2002 as a routine for all repeat biopsies.17 Since our initial studies identified no unique cancer in parasagittal cores from the mid gland or base, we decreased the number of cores from these sectors. This yielded a biopsy scheme of 20 cores focused on the lateral and apical aspects of the gland, as described.12 Briefly, 5 sectors were biopsied on each side, typically including the lateral base (2 cores), lateral mid zone (3), apex (3), parasagittal mid zone (1) and parasagittal base (1) (see figure). Clinically insignificant cancer was defined as Gleason sum less than 7, 3 or fewer positive cores and a maximum of 50% or less of cancer in any positive core. We used these criteria in a previously published study.18
PATIENTS AND METHODS Study Population A total of 1,462 patients underwent repeat PBx from March 2000 to April 2010 after initially negative PBx. Of the patients 406 were excluded from analysis since the number or distribution of cores was adjusted by prostate size, hypoechoic lesions on TRUS or suspicious nodules on DRE to provide direct comparison of the 2 protocols. Thus, 1,056 patients met study criteria, defined as standardized extended or saturation TRUS guided PBx after initial biopsy was negative for PCa. Patients were not randomized but rather prospectively evaluated for these outcomes in our institutional review board approved, Health Insurance Portability and Accountability Act compliant PBx database. Indications for second biopsy included previous suspicious pathological findings and/or clinical indications such as abnormal DRE, persistently increased PSA and PSA increasing greater than 0.75 ng/ml annually. Initially suspicious pathological findings were classified as ASAP with or without HGPIN, or as HGPIN exclusively. No study
851
Most common protocol for 20-core saturation PBx
852
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
Table 1. Study population baseline clinical characteristics by extended and saturation PBx Overall No. pts. (%) No. pos biopsy (%) Mean/median age (range) No. race (%): Black Asian White Other Mean/median PSA (range): Ng/ml % Free Density Mean/median No. biopsy cores (range) Mean/median cc vol (range): Total prostate Transitional zone No. DRE findings (%): No abnormality Abnormality Missing data No. initial PBx (%): Sextant Extended No. 1st PBx pathological features (%): Only HGPIN ASAP ⫾ HGPIN Benign
1,056 315 64.3/64 121 9 923 3
Extended PBx (100) (29.8) (41–84) (11.5) (0.8) (87.4) (0.3)
393 98 64.0/63
Saturation PBx
(37.2) (24.9) (41–84)
39 7 344 3
663 217 64.5/65
(9.9) (1.8) (87.5) (0.8)
p Value
(62.8) (32.7) (41–81)
82 2 579 0
(12.4) (0.3) (87.3)
6.43/5.55 (0.3–19.65) 17.09/16 (4–45) 0.15/0.13 (0.03–1.10) 17.6/20 (12–24)
6.42/5.40 (0.3–19.65) 16.33/15.50 (4–43) 0.15/0.13 (0.03–0.64) 12.3/12 (12–14)
6.43/5.69 (0.4–19.40) 17.33/16.00 (5–45) 0.16/0.13 (0.03–1.10) 20.7/20 (20–24)
47.4/42.3 25.7/20
48.3/45.0 25.3/19.7
47.0/42.0 26.0/20
(7–243) (4–154)
(9.8–146) (4.5–84.7)
(7–243) (4–154)
959 85 12
(90.8) (8) (1.2)
352 32 9
(89.6) (8.1) (2.3)
607 53 3
(91.5) (8) (0.5)
167 889
(15.8) (84.2)
62 331
(15.8) (84.2)
105 558
(15.8) (84.2)
196 109 751
(18.6) (10.3) (71.1)
74 42 277
(18.8) (10.7) (70.5)
122 67 474
(18.5) (10) (71.5)
Statistical Analysis For demographics in the 2 groups values are shown as the mean, median and range of continuous variables, and the frequency and percent of categorical variables. The demographics of the 2 biopsy groups were compared by the t test for continuous variables and by the chi-square or Fisher exact test for categorical variables with p ⬍0.05 considered statistically significant. The detection rate of overall and of clinically significant cancer was compared by the chi-square test in all cohorts or a specific cohort.
RESULTS PCa was detected in 315 of the 1,056 patients (29.8%). Biopsies were repeated a median of 1.2 years (range 0.5 to 3.4) after biopsy session 1. For the initial biopsy extended PBx was used as the original biopsy template in 889 men (84.2%) while in 167 (15.8%) an initial sextant biopsy scheme was used, primarily early in the study period before extended biopsy became widespread. Regarding pathological findings on the original biopsy 751 patients (71.1%) had completely benign biopsies with no ASAP or HGPIN, 109 had ASAP with or without HGPIN and 196 had HGPIN exclusively. PSA was 0.3 to 19.6 ng/ml at repeat biopsy. Table 1 lists clinical and demographic characteristics, showing that no statistically significant difference between the groups explained the significant difference in the cancer detection rates.
0.0075 0.32
0.23
0.97 0.23 0.56 ⬍0.0001
0.47 0.87 0.28
0.86 0.76 0.72
The saturation PBx group had a 31.3% higher detection rate compared to the extended PBx group (32.7% vs 24.9%, p ⫽ 0.0075). Table 2 shows the cancer yield in patients by initial biopsy findings. Of the 196 patients with a history of HGPIN exclusively 50 (25.5%) had cancer on repeat biopsy while cancer was detected in 36 of the 109 (33%) with ASAP with or without HGPIN. Of these presumably higher risk populations the PCa detection rate was higher in the saturation PBx group but did not achieve statistical significance (31.2% vs 23.3%, p ⫽ 0.13). In men with a completely normal initial biopsy saturation PBx showed significant improvement in PCa detection compared to that of extended PBx (33.3% vs 25.6%, p ⫽ 0.027). Of the 315 positive biopsies 119 (37.8%) revealed clinically insignificant cancer, as defined by the preTable 2. Detection rates in patients with benign, HGPIN and ASAP findings on initial PBx No. Pts/Total No. (%) Indication
Overall
Benign PBx 229/751 (30.5) Pathological findings: HGPIN 50/196 (25.5) ASAP ⫾ HGPIN 36/109 (33) Totals
86/305 (28.2)
Extended PBx Saturation PBx p value 71/277 (25.6)
158/474 (33.3)
0.027
16/74 (21.6) 11/42 (26.2)
34/122 (28) 25/67 (37.3)
0.33 0.23
27/116 (23.3)
59/189 (31.2)
0.13
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
determined parameters. There was a trend toward increased detection of clinically insignificant cancer in saturation vs extended PBx cases (87 of 217 or 40.1% vs 32 of 98 or 32.6%) but this also did not attain statistical significance (p ⫽ 0.2).
DISCUSSION Regardless of the protocol used for initial PBx the false-negative rate was substantial with cancer missed during initial biopsy in at least a quarter of patients.7 Several groups reported that saturation PBx can diagnose previously unidentified cancers with a total detection rate of 25% to 41%.11–14 Despite the widespread assumption that saturation biopsy increases cancer detection compared to extended biopsy notably to our knowledge no group has actually compared cancer detection rates. To address this obvious shortcoming we compared extended PBx with 12 to 14 cores and saturation PBx with 20 to 24 in a clearly defined, heterogeneous population of men who underwent repeat biopsy after a single prior biopsy failed to diagnose PCa. In the current study PCa detection was significantly higher in the saturation PBx population. Several series showed that additional biopsy samples, particularly in the far lateral peripheral zone, may increase the diagnostic yield of initial PBx by 30% to 35%.19,20 As performed using our template, office based saturation biopsy basically adds additional lateral and apical cores to the standard 12-core biopsy that is widely practiced (see figure). Thus, it achieves more intense sampling of areas known to be common sites of cancer that elude traditional biopsy while maintaining the sites included in extended biopsy. An issue limiting saturation PBx has been concern about morbidity. Although the relationship between the biopsy protocol and the complication rate was not the focus of our study, in a recent series we found no increase in complications or pain based on the number of cores.21 This finding is consistent with other data in the literature showing that the complication rate counterintuitively is not related to the number of cores.22 The PCa detection rate progressively decreases with each subsequent session in patients who undergo multiple repeat biopsies. Roehl et al reported that the detection rate decreased from 30% in the first biopsy to 7% after 6 sextant biopsy sessions.7 Similarly Djavan et al noted a detection rate of 22%, 10%, 5% and 4% at biopsy sessions 1 to 4, respectively, while identifying significant malignancy was uncommon after 2 negative biopsies.8 These data influenced our decision to limit the study population to patients undergoing only the second overall biopsy. Several issues in the current report differ substantially from the existing saturation biopsy literature.
853
Unlike previous series that assessed saturation PBx only after sextant biopy,9,13 in our study 84.2% of the patients initially underwent extended PBx, consistent with the current standard of care for initial biopsy.10 Walz et al reported a 41% cancer detection rate for saturation14 but, as in all other reports in the literature, they did not compare it to the detection rate in their extended biopsy cases. This indicates the challenge when assuming whether the detection rate is high or low, since to our knowledge there is no way to know the underlying rate of unrecognized cancer unless a comparison is made. The single study that has been misinterpreted as actually comparing detection rates was done by Pepe and Aragona.23 Although they reported doubling the PCa detection rate using saturation PBx, all saturation biopsies were transperineal, which is a completely different procedure than the method in our study. We believe that the confusion regarding that report is that the investigators used TRUS for guidance only and cores were obtained via the transperineal and not the transrectal approach with the patient under anesthesia. In our study all patients underwent transrectal saturation biopsy under periprostatic block. Thus, to our knowledge we report the first comparison of office based transrectal saturation biopsy and extended biopsy cancer detection rates. Our overall cancer detection rates in patients in whom the initial biopsy revealed HGPIN and ASAP were 25.5% and 33%, respectively, consistent with published data.24 Although the study was not designed or statistically powered for subanalysis of these high risk subpopulations, saturation biopsy also maintained its superior detection rate in these patients. The detection of clinically insignificant PCa is an inevitable risk of initial or repeat biopsy. Singh et al reported that this risk increased from 22.7% to 33.5% when increasing the number of cores from 6 to 12.25 Other reports suggest that saturation PBx may not increase the detection of clinically insignificant tumors.10,26 However, based on the predetermined published criteria in our study18 saturation PBx detected more cases of insignificant cancer. Although this did not attain statistical significance, the study was not powered for this and so conclusions about this aspect should be tempered. We believe that saturation biopsy carries a risk of increased detection of clinically insignificant cancer, although this did not attain statistical significance. We maintain our strong belief that PCa detection and treatment should always be considered independent processes, as advocated by Carroll.27 We actively pursue less rigorous management options such as active surveillance for tumors that appear to pose little threat to patient health, regardless of whether the biopsy is initial or repeat. Our study has some limitations. Data were derived from an institutional review board approved
854
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
database. Instead of having a mandated template for each scheme, attending urologist preference was the main determinant of the protocol. Possibly patients in whom additional cores were obtained due to abnormal DRE or ultrasound findings might have had different results. However, there was no difference in the demographic or clinical characteristics of the compared groups (table 1). We also eliminated outliers to provide a comparison of similar groups. Furthermore, when we performed the same analysis including an additional 406 patients, results were unchanged (unpublished data). Nevertheless, based on the potential heterogeneity of other biopsy templates we focused only on the 12 to 14-core cohort compared to the 20 to 24-core cohort. The number or percent of positive cores may be a false surrogate for clinically insignificant PCa. It must be recognized that there is no universally accepted definition of clinically insignificant cancer. To define clinically insignificant PCa we used the criteria from a previous published series,18 which evolved
since the original definitions were created. These criteria are based on the fact that the number of positive cores is not comparable with a variable denominator of between 6 and 24 cores. Moreover, we did not reevaluate these criteria in patients who elected radical prostatectomy. The discrepancy between biopsy and prostatectomy specimen findings would have intuitively changed the percent of men considered to have clinically insignificant cancer.
CONCLUSIONS As described, office based transrectal saturation PBx using only periprostatic block for anesthesia showed significantly superior cancer detection after initially negative biopsy. With no noted increase in complications21 there is little reason that its use should be limited to cases persistently suspicious for malignancy after multiple negative repeat biopsies. The detection of clinically insignificant cancer should be weighed against the risk of missing significant cases.
REFERENCES 1. Hodge KK, McNeal JE, Terris MK et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142: 71. 2. Keetch DW, Catalona WJ and Smith DS: Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 1994; 151: 1571. 3. Babaian RJ, Toi A, Kamoi K et al: A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000; 163: 152. 4. Epstein JI, Walsh PC and Carter HB: Importance of posterolateral needle biopsies in the detection of prostate cancer. Urology 2001; 57: 1112. 5. Gore JL, Shariat SF, Miles BJ et al: Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165: 1554. 6. Naughton CK, Miller DC, Mager DE et al: A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol 2000; 164: 388. 7. Roehl KA, Antenor JA and Catalona WJ: Serial biopsy results in prostate cancer screening study. J Urol 2002; 167: 2435. 8. Djavan B, Ravery V, Zlotta A et al: Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001; 166: 1679. 9. Borboroglu PG, Comer SW, Riffenburgh RH et al: Extensive repeat transrectal ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. J Urol 2000; 163: 158.
10. Jones JS, Patel A, Schoenfield L et al: Saturation technique does not improve cancer detection as an initial prostate biopsy strategy. J Urol 2006; 175: 485. 11. Rabets JC, Jones JS, Patel A et al: Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. J Urol 2004; 172: 94. 12. Patel AR, Jones JS, Rabets J et al: Parasagittal biopsies add minimal information in repeat saturation prostate biopsy. Urology 2004; 63: 87. 13. Stewart CS, Leibovich BC, Weaver AL et al: Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies. J Urol 2001; 166: 86. 14. Walz J, Graefen M, Chun FK et al: High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series. Eur Urol 2006; 50: 498. 15. Scattoni V, Maccagnano C, Zanni G et al: Is extended and saturation biopsy necessary? Int J Urol 2010; 17: 447. 16. Scattoni V, Zlotta A, Montironi R et al: Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. Urology 2007; 52: 1309. 17. Jones JS, Oder M and Zippe CD: Saturation prostate biopsy with periprostatic block can be performed in office. J Urol 2002; 168: 2108. 18. Tan N, Lane BR, Li J et al: Prostate cancers diagnosed at repeat biopsy are smaller and less likely to be high grade. J Urol 2008; 180: 1325. 19. Eskew LA, Bare RL and McCullough DL: Systematic 5 region prostate biopsy is superior to sex-
tant method for diagnosing carcinoma of the prostate. J Urol 1997; 157: 199. 20. Levine MA, Ittman M, Melamed J et al: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998; 159: 471. 21. Zaytoun OM, Anil T, Moussa AS et al: Morbidity of prostate biopsy after simplified versus complex preparation protocols: assessment of risk factors. Urology 2011; 77: 910. 22. Chiang N, Chang SJ, Pu S et al: Major complications and associated risk factors of transrectal ultrasound guided prostate needle biopsy: a retrospective study of 1,875 cases in Taiwan. J Formos Med Assoc 2007; 106: 929. 23. Pepe P and Aragona F: Saturation prostate needle biopsy and prostate cancer. Detection at initial and repeat evaluation. Urology 2007; 70: 1131. 24. Epstein JI and Herawi M: Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006; 175: 820. 25. Singh H, Canto EI, Shariat SF et al: Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. J Urol 2004; 171: 1089. 26. Taylor JA, Gancarczyk KJ, Fant GV et al: Increasing the number of core samples taken at prostate needle biopsy enhances the detection of clinically significant prostate cancer. Urology 2002; 60: 841. 27. Carroll PR: Early stage prostate cancer: do we have a problem with over-detection, over treatment or both? J Urol 2005; 173: 1061.
Abbreviations and Acronyms ASAP ⫽ atypical small acinar proliferation DRE ⫽ digital rectal examination HGPIN ⫽ high grade prostatic intraepithelial neoplasia PBx ⫽ prostate biopsy PCa ⫽ prostate cancer PSA ⫽ prostate specific antigen TRUS ⫽ transrectal ultrasound Submitted for publication January 13, 2011. Study received institutional review board approval. * Correspondence: Department of Regional Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave., A100, Cleveland Ohio 44195 (telephone: 216-444-2470; FAX: 216-445-2267; e-mail: [email protected]). † Financial interest and/or other relationship with Pfizer, Cook, Abbott, Endocare and GTx.
For another article on a related topic see page 1093.
Purpose: Multiple studies have shown significant prostate cancer detection for repeat biopsy. However, the best approach regarding core number and location remains controversial. Transrectal saturation biopsy is believed to increase cancer detection but to our knowledge no studies comparing it to 12 to 14-core extended biopsy have been published. We compared saturation and extended repeat biopsy protocols after initially negative biopsy. Materials and Methods: A total of 1,056 men underwent prostate biopsy after initially negative biopsy. The extended biopsy group included 393 men with 12 to 14-core repeat biopsy. The saturation biopsy group included 663 men with 20 to 24-core repeat biopsy. We analyzed demographics and prostate cancer between the 2 groups. We compared prostate cancer detection in patients with previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia as well as the risk of detecting clinically insignificant tumors. Results: Prostate cancer was detected in 315 of the 1,056 patients (29.8%). Saturation biopsy detected almost a third more cancers (32.7% vs 24.9%, p ⫽ 0.0075). In patients with a benign initial biopsy saturation biopsy achieved significantly greater prostate cancer detection (33.3% vs 25.6%, p ⫽ 0.027). For previous atypical small acinar proliferation and/or high grade prostatic intraepithelial neoplasia there was a trend toward higher prostate cancer detection rate in the saturation group but it did not attain statistical significance (31.2% vs 23.3%, p ⫽ 0.13). Of 315 positive biopsies 119 (37.8%) revealed clinically insignificant cancer (40.1% vs 32.6%, p ⫽ 0.2). Conclusions: Compared to extended biopsy, office based saturation biopsy significantly increases cancer detection on repeat biopsy. The potential for increased detection of clinically insignificant cancer should be weighed against missing significant cases. Key Words: prostate, prostatic neoplasms, biopsy, physicians’ offices, reoperation
850
www.jurology.com
AFTER its introduction by Hodge et al1 sextant PBx remained the mainstay of PCa diagnosis for several years. However, several investigators reported a high probability that this limited parasagittal scheme would miss cancer.2,3 Currently initial PBx should include at least 10 to 14 ex-
tended cores, including the lateral and anterior prostate zones, based on superior cancer detection rates.4,5 Even with the widespread application of extended PBx it is well recognized that many PCa cases are still missed at initial PBx due to sampling error and, thus, negative PBx does
0022-5347/11/1863-0850/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 850-854, September 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.04.069
AND
RESEARCH, INC.
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
not exclude cancer.6 A challenging dilemma facing urologists is the treatment of patients with initially negative PBx but in whom there remains suspicion for PCa. This suspicion is usually based on clinical and/or pathological indicators, ie DRE, increased PSA or previous biopsy showing ASAP and/or HGPIN. Studies describe a significant cancer detection rate of repeat biopsy in those populations.2,7 However, to our knowledge the best approach to repeat PBx remains undefined. Of all repeat biopsies that patients may undergo the initial repeat PBx (second overall biopsy) is characterized by the highest PCa detection7,8 The concept of increasing the number of cores has led to the emergence of transrectal saturation PBx, in which 20 or more cores are obtained in systematic fashion.9 Although we reported that saturation PBx does not improve cancer detection as an initial biopsy strategy,10 our series and several others11–14 suggested that saturation PBx enhances cancer detection in a repeat PBx population. With improvement in periprostatic block, concern about the morbidity of saturation biopsy appears unfounded. The safety and efficacy of saturation PBx are well established in many series while counterintuitively the complication rate is not higher than that of extended PBx.15,16 Also, saturation PBx can be safely and effectively done in the office using local anesthesia.17 Although it has been assumed that saturation PBx ensures a superior PCa detection rate at repeat biopsy, data comparing its cancer detection rate to that of extended repeat biopsy are lacking. We compared the results of extended and saturation PBx protocols in a first repeat PBx population.
patients received hormonal manipulation between the 2 biopsies. During the study period we recommended routine delayed interval biopsy 2 to 3 years after initial biopsy in men with HGPIN based on studies showing significant cancer detection at these intervals. In patients with initially detected ASAP we recommended repeat biopsy 6 month after the first PBx. In patients with initially benign biopsy findings the time of repeat biopsy was tailored by the risk indicators in each individual.
PBx and Patient Grouping The attending urologist practice pattern was the major factor determining the decision to perform repeat biopsy as well as the sample number and site. All TRUS guided biopsies were performed in an office setting with periprostatic block used routinely since 2002.17 The 12 to 14-core template obtained medial and lateral cores on each side from the base, mid gland and apex while in a few patients an additional core was obtained on each side of the extreme apex. Most clinicians used an extended template of 12 or 14 cores consistently during the study period and others used saturation biopsy for repeat biopsy. Patients were divided into 2 groups, including 393 with a 12 to 14-core biopsy scheme (extended PBx group) and 663 with a 20 to 24-core biopsy scheme (saturation PBx group). Based on early initial success several of our urologists began to perform 24-core saturation PBx in 2002 as a routine for all repeat biopsies.17 Since our initial studies identified no unique cancer in parasagittal cores from the mid gland or base, we decreased the number of cores from these sectors. This yielded a biopsy scheme of 20 cores focused on the lateral and apical aspects of the gland, as described.12 Briefly, 5 sectors were biopsied on each side, typically including the lateral base (2 cores), lateral mid zone (3), apex (3), parasagittal mid zone (1) and parasagittal base (1) (see figure). Clinically insignificant cancer was defined as Gleason sum less than 7, 3 or fewer positive cores and a maximum of 50% or less of cancer in any positive core. We used these criteria in a previously published study.18
PATIENTS AND METHODS Study Population A total of 1,462 patients underwent repeat PBx from March 2000 to April 2010 after initially negative PBx. Of the patients 406 were excluded from analysis since the number or distribution of cores was adjusted by prostate size, hypoechoic lesions on TRUS or suspicious nodules on DRE to provide direct comparison of the 2 protocols. Thus, 1,056 patients met study criteria, defined as standardized extended or saturation TRUS guided PBx after initial biopsy was negative for PCa. Patients were not randomized but rather prospectively evaluated for these outcomes in our institutional review board approved, Health Insurance Portability and Accountability Act compliant PBx database. Indications for second biopsy included previous suspicious pathological findings and/or clinical indications such as abnormal DRE, persistently increased PSA and PSA increasing greater than 0.75 ng/ml annually. Initially suspicious pathological findings were classified as ASAP with or without HGPIN, or as HGPIN exclusively. No study
851
Most common protocol for 20-core saturation PBx
852
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
Table 1. Study population baseline clinical characteristics by extended and saturation PBx Overall No. pts. (%) No. pos biopsy (%) Mean/median age (range) No. race (%): Black Asian White Other Mean/median PSA (range): Ng/ml % Free Density Mean/median No. biopsy cores (range) Mean/median cc vol (range): Total prostate Transitional zone No. DRE findings (%): No abnormality Abnormality Missing data No. initial PBx (%): Sextant Extended No. 1st PBx pathological features (%): Only HGPIN ASAP ⫾ HGPIN Benign
1,056 315 64.3/64 121 9 923 3
Extended PBx (100) (29.8) (41–84) (11.5) (0.8) (87.4) (0.3)
393 98 64.0/63
Saturation PBx
(37.2) (24.9) (41–84)
39 7 344 3
663 217 64.5/65
(9.9) (1.8) (87.5) (0.8)
p Value
(62.8) (32.7) (41–81)
82 2 579 0
(12.4) (0.3) (87.3)
6.43/5.55 (0.3–19.65) 17.09/16 (4–45) 0.15/0.13 (0.03–1.10) 17.6/20 (12–24)
6.42/5.40 (0.3–19.65) 16.33/15.50 (4–43) 0.15/0.13 (0.03–0.64) 12.3/12 (12–14)
6.43/5.69 (0.4–19.40) 17.33/16.00 (5–45) 0.16/0.13 (0.03–1.10) 20.7/20 (20–24)
47.4/42.3 25.7/20
48.3/45.0 25.3/19.7
47.0/42.0 26.0/20
(7–243) (4–154)
(9.8–146) (4.5–84.7)
(7–243) (4–154)
959 85 12
(90.8) (8) (1.2)
352 32 9
(89.6) (8.1) (2.3)
607 53 3
(91.5) (8) (0.5)
167 889
(15.8) (84.2)
62 331
(15.8) (84.2)
105 558
(15.8) (84.2)
196 109 751
(18.6) (10.3) (71.1)
74 42 277
(18.8) (10.7) (70.5)
122 67 474
(18.5) (10) (71.5)
Statistical Analysis For demographics in the 2 groups values are shown as the mean, median and range of continuous variables, and the frequency and percent of categorical variables. The demographics of the 2 biopsy groups were compared by the t test for continuous variables and by the chi-square or Fisher exact test for categorical variables with p ⬍0.05 considered statistically significant. The detection rate of overall and of clinically significant cancer was compared by the chi-square test in all cohorts or a specific cohort.
RESULTS PCa was detected in 315 of the 1,056 patients (29.8%). Biopsies were repeated a median of 1.2 years (range 0.5 to 3.4) after biopsy session 1. For the initial biopsy extended PBx was used as the original biopsy template in 889 men (84.2%) while in 167 (15.8%) an initial sextant biopsy scheme was used, primarily early in the study period before extended biopsy became widespread. Regarding pathological findings on the original biopsy 751 patients (71.1%) had completely benign biopsies with no ASAP or HGPIN, 109 had ASAP with or without HGPIN and 196 had HGPIN exclusively. PSA was 0.3 to 19.6 ng/ml at repeat biopsy. Table 1 lists clinical and demographic characteristics, showing that no statistically significant difference between the groups explained the significant difference in the cancer detection rates.
0.0075 0.32
0.23
0.97 0.23 0.56 ⬍0.0001
0.47 0.87 0.28
0.86 0.76 0.72
The saturation PBx group had a 31.3% higher detection rate compared to the extended PBx group (32.7% vs 24.9%, p ⫽ 0.0075). Table 2 shows the cancer yield in patients by initial biopsy findings. Of the 196 patients with a history of HGPIN exclusively 50 (25.5%) had cancer on repeat biopsy while cancer was detected in 36 of the 109 (33%) with ASAP with or without HGPIN. Of these presumably higher risk populations the PCa detection rate was higher in the saturation PBx group but did not achieve statistical significance (31.2% vs 23.3%, p ⫽ 0.13). In men with a completely normal initial biopsy saturation PBx showed significant improvement in PCa detection compared to that of extended PBx (33.3% vs 25.6%, p ⫽ 0.027). Of the 315 positive biopsies 119 (37.8%) revealed clinically insignificant cancer, as defined by the preTable 2. Detection rates in patients with benign, HGPIN and ASAP findings on initial PBx No. Pts/Total No. (%) Indication
Overall
Benign PBx 229/751 (30.5) Pathological findings: HGPIN 50/196 (25.5) ASAP ⫾ HGPIN 36/109 (33) Totals
86/305 (28.2)
Extended PBx Saturation PBx p value 71/277 (25.6)
158/474 (33.3)
0.027
16/74 (21.6) 11/42 (26.2)
34/122 (28) 25/67 (37.3)
0.33 0.23
27/116 (23.3)
59/189 (31.2)
0.13
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
determined parameters. There was a trend toward increased detection of clinically insignificant cancer in saturation vs extended PBx cases (87 of 217 or 40.1% vs 32 of 98 or 32.6%) but this also did not attain statistical significance (p ⫽ 0.2).
DISCUSSION Regardless of the protocol used for initial PBx the false-negative rate was substantial with cancer missed during initial biopsy in at least a quarter of patients.7 Several groups reported that saturation PBx can diagnose previously unidentified cancers with a total detection rate of 25% to 41%.11–14 Despite the widespread assumption that saturation biopsy increases cancer detection compared to extended biopsy notably to our knowledge no group has actually compared cancer detection rates. To address this obvious shortcoming we compared extended PBx with 12 to 14 cores and saturation PBx with 20 to 24 in a clearly defined, heterogeneous population of men who underwent repeat biopsy after a single prior biopsy failed to diagnose PCa. In the current study PCa detection was significantly higher in the saturation PBx population. Several series showed that additional biopsy samples, particularly in the far lateral peripheral zone, may increase the diagnostic yield of initial PBx by 30% to 35%.19,20 As performed using our template, office based saturation biopsy basically adds additional lateral and apical cores to the standard 12-core biopsy that is widely practiced (see figure). Thus, it achieves more intense sampling of areas known to be common sites of cancer that elude traditional biopsy while maintaining the sites included in extended biopsy. An issue limiting saturation PBx has been concern about morbidity. Although the relationship between the biopsy protocol and the complication rate was not the focus of our study, in a recent series we found no increase in complications or pain based on the number of cores.21 This finding is consistent with other data in the literature showing that the complication rate counterintuitively is not related to the number of cores.22 The PCa detection rate progressively decreases with each subsequent session in patients who undergo multiple repeat biopsies. Roehl et al reported that the detection rate decreased from 30% in the first biopsy to 7% after 6 sextant biopsy sessions.7 Similarly Djavan et al noted a detection rate of 22%, 10%, 5% and 4% at biopsy sessions 1 to 4, respectively, while identifying significant malignancy was uncommon after 2 negative biopsies.8 These data influenced our decision to limit the study population to patients undergoing only the second overall biopsy. Several issues in the current report differ substantially from the existing saturation biopsy literature.
853
Unlike previous series that assessed saturation PBx only after sextant biopy,9,13 in our study 84.2% of the patients initially underwent extended PBx, consistent with the current standard of care for initial biopsy.10 Walz et al reported a 41% cancer detection rate for saturation14 but, as in all other reports in the literature, they did not compare it to the detection rate in their extended biopsy cases. This indicates the challenge when assuming whether the detection rate is high or low, since to our knowledge there is no way to know the underlying rate of unrecognized cancer unless a comparison is made. The single study that has been misinterpreted as actually comparing detection rates was done by Pepe and Aragona.23 Although they reported doubling the PCa detection rate using saturation PBx, all saturation biopsies were transperineal, which is a completely different procedure than the method in our study. We believe that the confusion regarding that report is that the investigators used TRUS for guidance only and cores were obtained via the transperineal and not the transrectal approach with the patient under anesthesia. In our study all patients underwent transrectal saturation biopsy under periprostatic block. Thus, to our knowledge we report the first comparison of office based transrectal saturation biopsy and extended biopsy cancer detection rates. Our overall cancer detection rates in patients in whom the initial biopsy revealed HGPIN and ASAP were 25.5% and 33%, respectively, consistent with published data.24 Although the study was not designed or statistically powered for subanalysis of these high risk subpopulations, saturation biopsy also maintained its superior detection rate in these patients. The detection of clinically insignificant PCa is an inevitable risk of initial or repeat biopsy. Singh et al reported that this risk increased from 22.7% to 33.5% when increasing the number of cores from 6 to 12.25 Other reports suggest that saturation PBx may not increase the detection of clinically insignificant tumors.10,26 However, based on the predetermined published criteria in our study18 saturation PBx detected more cases of insignificant cancer. Although this did not attain statistical significance, the study was not powered for this and so conclusions about this aspect should be tempered. We believe that saturation biopsy carries a risk of increased detection of clinically insignificant cancer, although this did not attain statistical significance. We maintain our strong belief that PCa detection and treatment should always be considered independent processes, as advocated by Carroll.27 We actively pursue less rigorous management options such as active surveillance for tumors that appear to pose little threat to patient health, regardless of whether the biopsy is initial or repeat. Our study has some limitations. Data were derived from an institutional review board approved
854
TRANSRECTAL SATURATION BIOPSY PROSTATE CANCER DETECTION
database. Instead of having a mandated template for each scheme, attending urologist preference was the main determinant of the protocol. Possibly patients in whom additional cores were obtained due to abnormal DRE or ultrasound findings might have had different results. However, there was no difference in the demographic or clinical characteristics of the compared groups (table 1). We also eliminated outliers to provide a comparison of similar groups. Furthermore, when we performed the same analysis including an additional 406 patients, results were unchanged (unpublished data). Nevertheless, based on the potential heterogeneity of other biopsy templates we focused only on the 12 to 14-core cohort compared to the 20 to 24-core cohort. The number or percent of positive cores may be a false surrogate for clinically insignificant PCa. It must be recognized that there is no universally accepted definition of clinically insignificant cancer. To define clinically insignificant PCa we used the criteria from a previous published series,18 which evolved
since the original definitions were created. These criteria are based on the fact that the number of positive cores is not comparable with a variable denominator of between 6 and 24 cores. Moreover, we did not reevaluate these criteria in patients who elected radical prostatectomy. The discrepancy between biopsy and prostatectomy specimen findings would have intuitively changed the percent of men considered to have clinically insignificant cancer.
CONCLUSIONS As described, office based transrectal saturation PBx using only periprostatic block for anesthesia showed significantly superior cancer detection after initially negative biopsy. With no noted increase in complications21 there is little reason that its use should be limited to cases persistently suspicious for malignancy after multiple negative repeat biopsies. The detection of clinically insignificant cancer should be weighed against the risk of missing significant cases.
REFERENCES 1. Hodge KK, McNeal JE, Terris MK et al: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142: 71. 2. Keetch DW, Catalona WJ and Smith DS: Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J Urol 1994; 151: 1571. 3. Babaian RJ, Toi A, Kamoi K et al: A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000; 163: 152. 4. Epstein JI, Walsh PC and Carter HB: Importance of posterolateral needle biopsies in the detection of prostate cancer. Urology 2001; 57: 1112. 5. Gore JL, Shariat SF, Miles BJ et al: Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165: 1554. 6. Naughton CK, Miller DC, Mager DE et al: A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol 2000; 164: 388. 7. Roehl KA, Antenor JA and Catalona WJ: Serial biopsy results in prostate cancer screening study. J Urol 2002; 167: 2435. 8. Djavan B, Ravery V, Zlotta A et al: Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001; 166: 1679. 9. Borboroglu PG, Comer SW, Riffenburgh RH et al: Extensive repeat transrectal ultrasound guided prostate biopsy in patients with previous benign sextant biopsies. J Urol 2000; 163: 158.
10. Jones JS, Patel A, Schoenfield L et al: Saturation technique does not improve cancer detection as an initial prostate biopsy strategy. J Urol 2006; 175: 485. 11. Rabets JC, Jones JS, Patel A et al: Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. J Urol 2004; 172: 94. 12. Patel AR, Jones JS, Rabets J et al: Parasagittal biopsies add minimal information in repeat saturation prostate biopsy. Urology 2004; 63: 87. 13. Stewart CS, Leibovich BC, Weaver AL et al: Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies. J Urol 2001; 166: 86. 14. Walz J, Graefen M, Chun FK et al: High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series. Eur Urol 2006; 50: 498. 15. Scattoni V, Maccagnano C, Zanni G et al: Is extended and saturation biopsy necessary? Int J Urol 2010; 17: 447. 16. Scattoni V, Zlotta A, Montironi R et al: Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. Urology 2007; 52: 1309. 17. Jones JS, Oder M and Zippe CD: Saturation prostate biopsy with periprostatic block can be performed in office. J Urol 2002; 168: 2108. 18. Tan N, Lane BR, Li J et al: Prostate cancers diagnosed at repeat biopsy are smaller and less likely to be high grade. J Urol 2008; 180: 1325. 19. Eskew LA, Bare RL and McCullough DL: Systematic 5 region prostate biopsy is superior to sex-
tant method for diagnosing carcinoma of the prostate. J Urol 1997; 157: 199. 20. Levine MA, Ittman M, Melamed J et al: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998; 159: 471. 21. Zaytoun OM, Anil T, Moussa AS et al: Morbidity of prostate biopsy after simplified versus complex preparation protocols: assessment of risk factors. Urology 2011; 77: 910. 22. Chiang N, Chang SJ, Pu S et al: Major complications and associated risk factors of transrectal ultrasound guided prostate needle biopsy: a retrospective study of 1,875 cases in Taiwan. J Formos Med Assoc 2007; 106: 929. 23. Pepe P and Aragona F: Saturation prostate needle biopsy and prostate cancer. Detection at initial and repeat evaluation. Urology 2007; 70: 1131. 24. Epstein JI and Herawi M: Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006; 175: 820. 25. Singh H, Canto EI, Shariat SF et al: Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy. J Urol 2004; 171: 1089. 26. Taylor JA, Gancarczyk KJ, Fant GV et al: Increasing the number of core samples taken at prostate needle biopsy enhances the detection of clinically significant prostate cancer. Urology 2002; 60: 841. 27. Carroll PR: Early stage prostate cancer: do we have a problem with over-detection, over treatment or both? J Urol 2005; 173: 1061.