- Email: [email protected]
USE OF EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
0022-5347/05/1742-0505/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 174, 505–509, August 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000165385.53652.7a
USE OF EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY WENDY SIU, RODNEY L. DUNN, RAJAL B. SHAH
AND
JOHN T. WEI*, †
From the Departments of Urology and Pathology (RBS), University of Michigan, Ann Arbor, Michigan
ABSTRACT
Purpose: An extended prostate biopsy schema has been advocated at initial prostate biopsy to decrease the rate of false-negative cancer cases. However, critics have raised concerns that this may lead to the greater detection of clinically insignificant cancers. We examined the impact of using an extended pattern schema on cancer detection and also on the finding of smaller and clinically insignificant cancer. Materials and Methods: Clinical data, including patient age, race, prebiopsy prostate specific antigen (PSA), digital rectal examination, prostate volume, number of needle cores and biopsy findings were abstracted from the medical records of all patients who underwent prostate biopsy in a 5-year period. Extended pattern prostate biopsy was defined as more than 10 cores. Clinically insignificant cancer was defined as a maximal tumor dimension of 1.0 cm or less, Gleason sum 6 or less and organ confined disease at radical prostatectomy. Adjusted regression models were developed to assess the independent effects of using an extended biopsy pattern on the detection of cancer overall and on the detection of clinically insignificant cancer. Results: A total of 740 men with a mean age of 62.6 years were referred for prostate biopsy. Median PSA was 5.7 ng/ml and prostate volume was 39.7 cc. The OR for detecting prostate cancer was 1.55 (95% CI 1.09 to 2.19) for the extended pattern compared with standard biopsy. Of the subset of 136 patients who underwent radical prostatectomy 12.6% had clinically insignificant cancer. However, in contrast to overall cancer detection, extended pattern prostate biopsy was not found to be associated with an increased risk of detecting smaller or clinically insignificant cancer. PSA density was the single parameter found to be independently associated with the detection of clinically insignificant cancer (95% CI 0.20 to 0.98). Conclusions: Using an extended prostate biopsy pattern involving more than 10 cores increases the likelihood of detecting prostate cancer. A significant association between more needle cores at initial prostate biopsy and finding smaller and clinically insignificant cancer was not apparent. KEY WORDS: prostate, prostatic neoplasms, biopsy, diagnosis, prostate-specific antigen
The contemporary practice of medicine and surgery is based on the time honored principles of beneficence and nonmaleficence. The goal of prostate biopsy is to detect clinically significant cancers. However, given the indolent nature of most prostate cancers, it is possible that clinical manifestations may never occur during the lifetime of a patient. Therefore, when recommending prostate biopsy, urologists must consider the potential benefits while minimizing the risks, including the risks of subsequent treatment. Based on Surveillance, Epidemiology, and End Results data about 35% of men elect radical prostatectomy and 32% elect radiotherapy.1 Following radical prostatectomy 7% to 37% of men have urinary incontinence and 14% to 80% notice erectile dysfunction.2, 3 Of patients who choose external beam radiotherapy 9% to 19% report significant problems with bowel function, 2% to 2.5% report significant problems with urinary incontinence and 24% to 40% report significant problems with erectile dysfunction.4, 5 The introduction and refinement of template prostate biopsies have dramatically changed the practice of urology. In 1989 sextant prostate biopsy was established and it rapidly
became the standard over directed biopsies of hypoechoic lesions and palpable nodules.6 Based on this study others advocated an extended pattern technique at initial prostate biopsy to further increase the likelihood of detecting cancer. In a simulation model Daneshgari et al suggested that, although sextant biopsies were an improvement, they would still miss many cancers since only 20.3% of prostates had a tumor distribution that would be detected with the paramedian sextant template.7 Several others have since compared different biopsy techniques and defined biopsy strategies, which range from 88 to 139 cores. Critics of the extended prostate biopsy approach have used the theoretical argument that more clinically insignificant cancers must by definition be detected and they have pointed out that during the lifetime of a man his chance of being diagnosed with prostate cancer is 6 times greater than his likelihood of dying of it.10 The potential detection of clinically insignificant disease has understandably led some groups to specifically not support biopsy templates that involve an increased number of needle cores. However, the impact of these strategies on the detection of clinically insignificant disease at initial biopsy has not been well studied. To improve patient counseling we quantified the effect of the initial biopsy technique on overall cancer detection and on the finding of smaller and clinically insignificant cancers.
Submitted for publication September 16, 2004. Study received Institutional Review Board approval. * Correspondence: Department of Urology, Taubman Health Care Center, University of Michigan Health System, 1500 East Medical Center Dr., Ann Arbor, Michigan 48109-0330 (telephone: 734-615METHODS 3040; FAX: 734-936-9127; e-mail: [email protected]). All men who were referred to a tertiary care hospital for † Financial interest and/or other relationship with Laserscope, prostate biopsy between October 1997 and August 2003 were Sanofi, Calypso and Boehringer Ingelheim. 505
506
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
included in an Institutional Review Board approved database project. Reasons for biopsy were increased prostate specific antigen (PSA), abnormal digital rectal examination (DRE) and a family history of prostate cancer. Of these 1,060 patients we excluded men with prior biopsies, leaving a total of 740 who presented for initial biopsy. Clinical data, including patient age, race, prebiopsy PSA, DRE, transrectal ultrasound measured prostate volume and the number of needle cores were abstracted in an explicit review of the medical record. Pathological findings, including cancer status, Gleason score, the greatest percent of a core positive for cancer (GPC) and clinically significant vs clinically insignificant cancer, were obtained from the prostate cancer database at our institution. A total of 15 attending urologists performed biopsies at our institution during this period. The number of biopsies taken was determined clinically by the individual urologist. In some cases additional cores were obtained due to abnormal lesions on ultrasound and larger prostates. As defined by the National Comprehensive Cancer Network, an extended pattern is essentially a sextant template with at least 4 additional cores from the lateral peripheral zone as well as biopsies directed to lesions found on palpation or imaging.11 Based on the raw data, which revealed a bimodal distribution of needle cores with peaks at 6 and 12, reflecting a tendency to perform sextant or extended 12 core biopsy, we defined an extended pattern biopsy as a case in which more than 10 needle cores were taken. Additional immunostaining with basal cell marker antibodies K903 and P63 was performed as needed for small lesions to confirm the presence of cancer. GPC has been shown to be related to PSA recurrence-free survival.12 Low GPC is associated with smaller tumors and, therefore, it may be considered a surrogate for clinically insignificant cancers. In addition to Gleason score, GPC was also quantified for each case positive for cancer. A subset of 136 patients who were found to have prostate cancer then underwent radical prostatectomy at our institution. Prostate specimens were examined by pathologists and maximal tumor dimensions, final Gleason score, tumor margin status, lymph node involvement and seminal vesicle involvement were recorded. Clinically insignificant cancer was defined as fulfilling all of certain criteria, including a maximal dimensions of 1.0 cm or less at prostatectomy (ie a diameter of 1.0 cm or less, corresponding to a volume of 0.5 cc or less based on the geometric formula for a sphere, that is ⬃4/3r3), Gleason sum 6 or less and organ confined disease (no extraprostatic extension, lymph node or seminal vesicle involvement).13 Bivariate statistics (the t and chi-square tests) were used to identify the strongest predictors of cancer diagnosis. Backward stepwise logistic regression models were constructed to determine the adjusted OR of using an extended biopsy pattern on the overall detection of prostate cancer, the GPC and the detection of clinically insignificant cancer. Variables considered in the model building process were extended vs standard biopsy pattern, patient age, race, abnormal DRE, increased PSA, number of indicators for biopsy (0 or 1 vs 2 or more) and PSA density (PSAD). All statistical analyses were performed using SAS 9.0 (SAS Institute, Cary, North Carolina) with p of ⬍0.05 considered statistically significant. To be more conservative 2-sided tests for significance were used in all analyses. RESULTS
Table 1 shows the population of 740 men in the study and the subset of 136 who underwent radical prostatectomy, stratified by indications for initial biopsy and biopsy findings. There were several significant differences between the populations undergoing standard vs extended pattern biopsy at the initial setting (table 2).
TABLE 1. Demographics, indications for biopsy and biopsy findings in all subjects and in subset that underwent radical prostatectomy All Prostate Biopsy
Radical Prostatectomy
No. subjects 740 136 Mean age* 62.6 59.2 % Black 9.1 10.7 Median PSA (ng/ml) 5.7 5.2 Median prostate vol (cc)* 39.7 33.0 Median PSAD (ng/ml/cc)* 0.14 0.16 % Biopsy indications:† Abnormal DRE 17.1 17.1 Increased PSA* 86.4 92.3 Family history 0.8 0.0 % Biopsy Gleason score: 2–6 52.3 50.0 7 38.0 44.0 8–10 9.7 6.0 Median % biopsy GPC 40 40 * Statistically significant difference between those who did and did not undergo radical prostatectomy (p ⬍0.05). † Total equals greater than 100% since some patients had more than 1 indication for biopsy.
TABLE 2. Bivariate analyses of confounding effects of demographic and disease characteristics on biopsy technique Standard Technique
Extended Technique*
p Value
No. subjects 367 293 Mean age 63.3 61.3 ⬍0.01 % Black 7.4 11.1 0.26 Median PSA (ng/ml) 5.9 5.5 0.78 Median prostate vol (cc) 37.3 42.7 ⬍0.01 % More than 1 biopsy indication 9.5 7.2 0.32 Median PSAD (ng/ml/cc) 0.15 0.13 0.04 % Biopsy indications: Abnormal DRE 18.7 14.7 0.21 Increased PSA 83.2 90.8 0.01 Family history 0.3 1.4 0.18 % Mean biopsy Gleason score: 0.20 2–6 52.7 45.9 7 39.0 42.2 8–10 8.2 11.9 Median % biopsy GPC 40 50 0.14 * Sextant biopsies plus sampling of anterior horn, lateral apex and lateral base (greater than 10 cores) and 80 subjects could not be classified due to incomplete biopsy technique information.
Table 3 lists the unadjusted associations between prebiopsy variables and overall prostate cancer detection, clinically insignificant cancer detection and GPC 10% or less. There were no significant differences between using a standard vs extended pattern biopsy technique at the initial setting when analyzing the detection of overall prostate cancer (p ⫽ 0.113), clinically insignificant cancer detection (p ⫽ 0.29) or GPC (p ⫽ 0.14) (figs. 1 and 2). To account for potential confounding in this study due to variations in the group of urologists obtaining biopsies as well as demographic differences in patients electing radical prostatectomy adjusted models were constructed to examine the independent association of biopsy technique on each of our study end points. The final multivariable regression models demonstrated a significant independent effect of extended pattern biopsy at the initial setting on overall cancer detection with an OR of 1.55 (95% CI 1.09 to 2.19). No significant association was observed between an extended biopsy technique and the detection of smaller (95% CI 0.39 to 1.21) or insignificant (95% CI 0.54 to 4.54) cancers. PSAD was the single parameter found to be independently associated with the detection of overall cancer and clinically insignificant cancer. PSAD greater than 0.1 had an OR of 1.63 (95% CI 1.37 to 1.94) for the detection of overall cancer. Moreover, it was also inversely associated with the detection
507
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
TABLE 3. Unadjusted associations between demographic and disease factors, and detection of cancer, clinically insignificant cancer and smaller cancers based on GPC % Overall Detection
p Value
% Clinically Insignificant Detection
p Value
% GPC 10% or Less*
No. subjects 740 136 317 Overall rate 44.5 12.6 32.8 Age older than 60 49.6 ⬍0.01 7.8 0.13 29.5 Black race 50.0 0.04 15.4 0.15 21.4 Prostate vol greater than 40 cc 33.4 ⬍0.01 24.2 0.07 30.6 PSAD greater than 0.1 ng/ml/cc 50.5 ⬍0.01 12.2 0.35 25.4 Biopsy indications: Abnormal DRE 44.6 0.53 9.1 0.74 20.0 Increased PSA 45.2 ⬍0.01 12.7 ⬎0.99 29.0 More than 1 indication 63.6 ⬍0.01 7.7 0.68 16.1 * Cutoff was chosen because 10% was 25th percentile of standard biopsy group and median value in insignificant cancer group.
p Value
0.07 0.75 0.78 0.02 0.15 0.79 0.10
FIG. 1. Unadjusted cancer detection rates detection for standard and extended biopsy techniques (overall and clinically insignificant cancer detection p ⫽ 0.113 and 0.29, respectively).
FIG. 3. Relationships between PSAD, and detection of prostate cancer overall and clinically insignificant cancers.
FIG. 2. GPC of standard and extended biopsy techniques (p ⫽ 0.14).
of insignificant disease with an OR of 0.44 (95% CI 0.20 to 0.98). Specifically at higher PSAD cancer was not only more likely to be detected, but it was also more likely to be significant disease (fig. 3). DISCUSSION
Our findings demonstrate that an extended pattern prostate biopsy technique significantly increases the likelihood of overall cancer detection at initial biopsy. Eskew et al also
advocated an extended pattern.14 They found a statistically significant advantage (35% greater detection) with the additional cores of a 5 region biopsy.9 On the other hand, comparisons of cancer detection rates using a 12 core schema vs sextant biopsy showed no such improvement. This may be due to the fact that these patients were part of a screening population, in contrast to being referred specifically for prostate biopsy. With their 11 site pattern technique Babaian et al detected 31% more cancers at initial biopsy compared with sextant biopsy, although this increase in cancer detection was not statistically significant.15 It should be noted that their template differed somewhat with additional cores obtained from the midline and transition zone, and 2 taken from the anterior horns. Interestingly the more recent results of this group demonstrated a significant increase in cancer detection using their 11 core scheme.16 However, the study population included patients undergoing initial and repeat prostate biopsy.
508
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
An equally important finding was the lack of an association between an extended biopsy technique and the detection of smaller or clinically insignificant tumors. Although critics warn of the potential of finding insignificant disease, to date no one has been able to detect this phenomenon. Eskew et al compared the pathology results of prostatectomy specimens detected by their 5 region biopsy vs a sextant biopsy technique.17 They noted no significant difference in tumor volume, Gleason grade or tumor stage. Naughton et al assessed men who underwent more than 6 biopsies during 1 or more biopsy sessions.18 Their analyses did not detect any difference compared with the sextant group in terms of Gleason score, cancer volume and organ confinement of possibly harmless cancer (tumor volume less than 0.2 cc, Gleason score less 7 and no capsular penetration). Naya et al found no disparity in the incidence of extraprostatic extension of cancers detected with the sextant vs the extended template.16 Furthermore, the additional cores of the extended biopsy technique enhanced sensitivity for predicting extraprostatic extension. Our conclusions expand the studies of these groups by focusing on extended cores at initial biopsy and then defining small tumors based on GPC as well as the complete Epstein classification of insignificant tumors.13 The National Comprehensive Cancer Network Practice Guidelines for Prostate Cancer Early Detection suggest an extended pattern biopsy comprising sextant cores along with sampling of the lateral peripheral zone and lesions suspicious on palpation or imaging.11 Our findings support these practice guidelines and our current report provides evidence that an extended pattern technique increases overall cancer detection without any significant increase in detecting clinically insignificant disease. By increasing the likelihood of cancer detection at initial biopsy we decrease substantially the proportion of men with negative biopsies who then undergo repeat biopsy because of persistently increasing PSA or abnormal DRE. It has been demonstrated that abnormal PSA is associated with cancer worry. There are benefits that cannot be quantified, such as relieving the psychological stress of patients who are concerned about the false-negative rate inherent in the standard sextant technique. Our findings of the usefulness of PSAD are consistent with those in prior studies.13 At lower PSAD prostate cancer was less likely to be detected but a greater proportion of them were insignificant cancers. PSAD greater than 0.2 was the threshold at which there was a lower likelihood of detecting insignificant cancer. Using 40 gm as the average prostate size a PSA of 8 ng/ml results in a PSAD of 0.2 and according to our results there was an approximately 23% chance of insignificant cancer. However, at PSA 12 ng/ml and PSAD 0.3 one would expect only about 3% insignificant disease. Beyond PSAD greater than 0.3 all cancers detected were clinically significant. When counseling patients who are considering definitive therapy for prostate cancer, the simple calculation of PSAD may be useful for determining whether the cancer detected by extended biopsies is potentially insignificant disease. This study has several limitations. 1) We did not investigate adverse effects at prostate biopsy that were directly related to obtaining additional biopsy cores. Common complications of prostate biopsy range from gross hematuria, which occurs in 12.8% of patients, to hospitalization for infection in 0.2%.11 Naughton et al did not observe any difference in morbidity when taking 12 vs 6 cores.19 On the other hand, Rodriguez et al found that fevers and chills were related to the number of biopsies.20 However, all of these patients were treated with antibiotics on an outpatient basis and none progressed to infectious sequelae. 2) Our results were based on a retrospective observational study with the potential for confounding due to individual physician practices. The extended pattern group had a lower mean age, higher median prostate volume, lower median
PSAD and a higher percent of patients with increased PSA as an indication for biopsy. These factors may have impacted the finding of insignificant disease. Therefore, we attempted to overcome these limitations with adjusted multivariable models. Furthermore, our definition of clinically insignificant cancer is based on surgical pathology results. Men who elected radical prostatectomy for therapy differed from the study population as a whole in having a lower mean age, lower median prostate volume and higher PSAD, while there was a higher percent with increased PSA. Thus, they may not be generalizable to all men who undergo a biopsy. CONCLUSIONS
An extended pattern prostate biopsy technique increases the cancer detection rates without a significant increase in clinically insignificant disease. PSAD may identify patients in whom insignificant disease is uncommon. More research is necessary to determine the optimal prostate biopsy strategy to balance all risks and benefits. Dr. James E. Montie reviewed the manuscript. REFERENCES
1. Stephenson, R. A.: Prostate cancer trends in the era of prostatespecific antigen. An update of incidence, mortality, and clinical factors from the SEER database. Urol Clin North Am, 29: 173, 2002 2. Hu, J. C., Elkin, E. P., Pasta, D. J., Lubeck, D. P., Kattan, M. W., Carroll, P. R. et al: Predicting quality of life after radical prostatectomy: results from CaPSURE. J Urol, 171: 703, 2004 3. Walsh, P. C.: Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate. J Urol, 163: 1802, 2000 4. Talcott, J. A., Rieker, P., Clark, J. A., Propert, K. J., Weeks, J. C., Beard, C. J. et al: Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study. J Clin Oncol, 16: 275, 1998 5. Hamilton, A. S., Stanford, J. L., Gilliland, F. D., Albertsen, P. C., Stephenson, R. A., Hoffman, R. M. et al: Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol, 19: 2517, 2001 6. Hodge, K. K., McNeal, J. E., Terris, M. K. and Stamey, T. A.: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol, 142: 71, 1989 7. Daneshgari, F., Taylor, G. D., Miller, G. J. and Crawford, E. D.: Computer simulation of the probability of detecting low volume carcinoma of the prostate with six random systematic core biopsies. Urology, 45: 604, 1995 8. Presti, J. C., Jr., Chang, J. J., Bhargava, V. and Shinohara, K.: The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol, 163: 163, 2000 9. 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 10. Talcott, J. A.: New era in prostate-cancer care: what we know and what we don’t. Lancet Oncol, 4: 204, 2003 11. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Available at www.nccn.org. Accessed June 2004 12. Nelson, C. P., Rubin, M. A., Strawderman, M., Montie, J. E. and Sanda, M. G.: Preoperative parameters for predicting early prostate cancer recurrence after radical prostatectomy. Urology, 59: 740, 2002 13. Epstein, J. I., Walsh, P. C., Carmichael, M. and Brendler, C. B.: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA, 271: 368, 1994 14. Naughton, C. K., Miller, D. C., Mager, D. E., Ornstein, D. K. and Catalona, W. J.: A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol, 164: 388, 2000 15. Babaian, R. J., Toi, A., Kamoi, K., Troncoso, P., Sweet, J., Evans, R. et al: A comparative analysis of sextant and an extended
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY 11-core multisite directed biopsy strategy. J Urol, 163: 152, 2000 16. Naya, Y., Ochiai, A., Troncoso, P. and Babaian, R. J.: A comparison of extended biopsy and sextant biopsy schemes for predicting the pathological stage of prostate cancer. J Urol, 171: 2203, 2004 17. Eskew, L. A., Woodruff, R. D., Bare, R. L. and McCullough, D. L.: Prostate cancer diagnosed by the 5 region biopsy method is significant disease. J Urol, 160: 794, 1998 18. Naughton, C. K., Smith, D. S., Humphrey, P. A., Catalona, W. J. and Keetch, D. W.: Clinical and pathologic tumor
509
characteristics of prostate cancer as a function of the number of biopsy cores: a retrospective study. Urology, 52: 808, 1998 19. Naughton, C. K., Ornstein, D. K., Smith, D. S. and Catalona, W. J.: Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores. J Urol, 163: 168, 2000 20. Rodriguez, L. V. and Terris, M. K.: Risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. J Urol, 160: 2115, 1998
Vol. 174, 505–509, August 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000165385.53652.7a
USE OF EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY WENDY SIU, RODNEY L. DUNN, RAJAL B. SHAH
AND
JOHN T. WEI*, †
From the Departments of Urology and Pathology (RBS), University of Michigan, Ann Arbor, Michigan
ABSTRACT
Purpose: An extended prostate biopsy schema has been advocated at initial prostate biopsy to decrease the rate of false-negative cancer cases. However, critics have raised concerns that this may lead to the greater detection of clinically insignificant cancers. We examined the impact of using an extended pattern schema on cancer detection and also on the finding of smaller and clinically insignificant cancer. Materials and Methods: Clinical data, including patient age, race, prebiopsy prostate specific antigen (PSA), digital rectal examination, prostate volume, number of needle cores and biopsy findings were abstracted from the medical records of all patients who underwent prostate biopsy in a 5-year period. Extended pattern prostate biopsy was defined as more than 10 cores. Clinically insignificant cancer was defined as a maximal tumor dimension of 1.0 cm or less, Gleason sum 6 or less and organ confined disease at radical prostatectomy. Adjusted regression models were developed to assess the independent effects of using an extended biopsy pattern on the detection of cancer overall and on the detection of clinically insignificant cancer. Results: A total of 740 men with a mean age of 62.6 years were referred for prostate biopsy. Median PSA was 5.7 ng/ml and prostate volume was 39.7 cc. The OR for detecting prostate cancer was 1.55 (95% CI 1.09 to 2.19) for the extended pattern compared with standard biopsy. Of the subset of 136 patients who underwent radical prostatectomy 12.6% had clinically insignificant cancer. However, in contrast to overall cancer detection, extended pattern prostate biopsy was not found to be associated with an increased risk of detecting smaller or clinically insignificant cancer. PSA density was the single parameter found to be independently associated with the detection of clinically insignificant cancer (95% CI 0.20 to 0.98). Conclusions: Using an extended prostate biopsy pattern involving more than 10 cores increases the likelihood of detecting prostate cancer. A significant association between more needle cores at initial prostate biopsy and finding smaller and clinically insignificant cancer was not apparent. KEY WORDS: prostate, prostatic neoplasms, biopsy, diagnosis, prostate-specific antigen
The contemporary practice of medicine and surgery is based on the time honored principles of beneficence and nonmaleficence. The goal of prostate biopsy is to detect clinically significant cancers. However, given the indolent nature of most prostate cancers, it is possible that clinical manifestations may never occur during the lifetime of a patient. Therefore, when recommending prostate biopsy, urologists must consider the potential benefits while minimizing the risks, including the risks of subsequent treatment. Based on Surveillance, Epidemiology, and End Results data about 35% of men elect radical prostatectomy and 32% elect radiotherapy.1 Following radical prostatectomy 7% to 37% of men have urinary incontinence and 14% to 80% notice erectile dysfunction.2, 3 Of patients who choose external beam radiotherapy 9% to 19% report significant problems with bowel function, 2% to 2.5% report significant problems with urinary incontinence and 24% to 40% report significant problems with erectile dysfunction.4, 5 The introduction and refinement of template prostate biopsies have dramatically changed the practice of urology. In 1989 sextant prostate biopsy was established and it rapidly
became the standard over directed biopsies of hypoechoic lesions and palpable nodules.6 Based on this study others advocated an extended pattern technique at initial prostate biopsy to further increase the likelihood of detecting cancer. In a simulation model Daneshgari et al suggested that, although sextant biopsies were an improvement, they would still miss many cancers since only 20.3% of prostates had a tumor distribution that would be detected with the paramedian sextant template.7 Several others have since compared different biopsy techniques and defined biopsy strategies, which range from 88 to 139 cores. Critics of the extended prostate biopsy approach have used the theoretical argument that more clinically insignificant cancers must by definition be detected and they have pointed out that during the lifetime of a man his chance of being diagnosed with prostate cancer is 6 times greater than his likelihood of dying of it.10 The potential detection of clinically insignificant disease has understandably led some groups to specifically not support biopsy templates that involve an increased number of needle cores. However, the impact of these strategies on the detection of clinically insignificant disease at initial biopsy has not been well studied. To improve patient counseling we quantified the effect of the initial biopsy technique on overall cancer detection and on the finding of smaller and clinically insignificant cancers.
Submitted for publication September 16, 2004. Study received Institutional Review Board approval. * Correspondence: Department of Urology, Taubman Health Care Center, University of Michigan Health System, 1500 East Medical Center Dr., Ann Arbor, Michigan 48109-0330 (telephone: 734-615METHODS 3040; FAX: 734-936-9127; e-mail: [email protected]). All men who were referred to a tertiary care hospital for † Financial interest and/or other relationship with Laserscope, prostate biopsy between October 1997 and August 2003 were Sanofi, Calypso and Boehringer Ingelheim. 505
506
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
included in an Institutional Review Board approved database project. Reasons for biopsy were increased prostate specific antigen (PSA), abnormal digital rectal examination (DRE) and a family history of prostate cancer. Of these 1,060 patients we excluded men with prior biopsies, leaving a total of 740 who presented for initial biopsy. Clinical data, including patient age, race, prebiopsy PSA, DRE, transrectal ultrasound measured prostate volume and the number of needle cores were abstracted in an explicit review of the medical record. Pathological findings, including cancer status, Gleason score, the greatest percent of a core positive for cancer (GPC) and clinically significant vs clinically insignificant cancer, were obtained from the prostate cancer database at our institution. A total of 15 attending urologists performed biopsies at our institution during this period. The number of biopsies taken was determined clinically by the individual urologist. In some cases additional cores were obtained due to abnormal lesions on ultrasound and larger prostates. As defined by the National Comprehensive Cancer Network, an extended pattern is essentially a sextant template with at least 4 additional cores from the lateral peripheral zone as well as biopsies directed to lesions found on palpation or imaging.11 Based on the raw data, which revealed a bimodal distribution of needle cores with peaks at 6 and 12, reflecting a tendency to perform sextant or extended 12 core biopsy, we defined an extended pattern biopsy as a case in which more than 10 needle cores were taken. Additional immunostaining with basal cell marker antibodies K903 and P63 was performed as needed for small lesions to confirm the presence of cancer. GPC has been shown to be related to PSA recurrence-free survival.12 Low GPC is associated with smaller tumors and, therefore, it may be considered a surrogate for clinically insignificant cancers. In addition to Gleason score, GPC was also quantified for each case positive for cancer. A subset of 136 patients who were found to have prostate cancer then underwent radical prostatectomy at our institution. Prostate specimens were examined by pathologists and maximal tumor dimensions, final Gleason score, tumor margin status, lymph node involvement and seminal vesicle involvement were recorded. Clinically insignificant cancer was defined as fulfilling all of certain criteria, including a maximal dimensions of 1.0 cm or less at prostatectomy (ie a diameter of 1.0 cm or less, corresponding to a volume of 0.5 cc or less based on the geometric formula for a sphere, that is ⬃4/3r3), Gleason sum 6 or less and organ confined disease (no extraprostatic extension, lymph node or seminal vesicle involvement).13 Bivariate statistics (the t and chi-square tests) were used to identify the strongest predictors of cancer diagnosis. Backward stepwise logistic regression models were constructed to determine the adjusted OR of using an extended biopsy pattern on the overall detection of prostate cancer, the GPC and the detection of clinically insignificant cancer. Variables considered in the model building process were extended vs standard biopsy pattern, patient age, race, abnormal DRE, increased PSA, number of indicators for biopsy (0 or 1 vs 2 or more) and PSA density (PSAD). All statistical analyses were performed using SAS 9.0 (SAS Institute, Cary, North Carolina) with p of ⬍0.05 considered statistically significant. To be more conservative 2-sided tests for significance were used in all analyses. RESULTS
Table 1 shows the population of 740 men in the study and the subset of 136 who underwent radical prostatectomy, stratified by indications for initial biopsy and biopsy findings. There were several significant differences between the populations undergoing standard vs extended pattern biopsy at the initial setting (table 2).
TABLE 1. Demographics, indications for biopsy and biopsy findings in all subjects and in subset that underwent radical prostatectomy All Prostate Biopsy
Radical Prostatectomy
No. subjects 740 136 Mean age* 62.6 59.2 % Black 9.1 10.7 Median PSA (ng/ml) 5.7 5.2 Median prostate vol (cc)* 39.7 33.0 Median PSAD (ng/ml/cc)* 0.14 0.16 % Biopsy indications:† Abnormal DRE 17.1 17.1 Increased PSA* 86.4 92.3 Family history 0.8 0.0 % Biopsy Gleason score: 2–6 52.3 50.0 7 38.0 44.0 8–10 9.7 6.0 Median % biopsy GPC 40 40 * Statistically significant difference between those who did and did not undergo radical prostatectomy (p ⬍0.05). † Total equals greater than 100% since some patients had more than 1 indication for biopsy.
TABLE 2. Bivariate analyses of confounding effects of demographic and disease characteristics on biopsy technique Standard Technique
Extended Technique*
p Value
No. subjects 367 293 Mean age 63.3 61.3 ⬍0.01 % Black 7.4 11.1 0.26 Median PSA (ng/ml) 5.9 5.5 0.78 Median prostate vol (cc) 37.3 42.7 ⬍0.01 % More than 1 biopsy indication 9.5 7.2 0.32 Median PSAD (ng/ml/cc) 0.15 0.13 0.04 % Biopsy indications: Abnormal DRE 18.7 14.7 0.21 Increased PSA 83.2 90.8 0.01 Family history 0.3 1.4 0.18 % Mean biopsy Gleason score: 0.20 2–6 52.7 45.9 7 39.0 42.2 8–10 8.2 11.9 Median % biopsy GPC 40 50 0.14 * Sextant biopsies plus sampling of anterior horn, lateral apex and lateral base (greater than 10 cores) and 80 subjects could not be classified due to incomplete biopsy technique information.
Table 3 lists the unadjusted associations between prebiopsy variables and overall prostate cancer detection, clinically insignificant cancer detection and GPC 10% or less. There were no significant differences between using a standard vs extended pattern biopsy technique at the initial setting when analyzing the detection of overall prostate cancer (p ⫽ 0.113), clinically insignificant cancer detection (p ⫽ 0.29) or GPC (p ⫽ 0.14) (figs. 1 and 2). To account for potential confounding in this study due to variations in the group of urologists obtaining biopsies as well as demographic differences in patients electing radical prostatectomy adjusted models were constructed to examine the independent association of biopsy technique on each of our study end points. The final multivariable regression models demonstrated a significant independent effect of extended pattern biopsy at the initial setting on overall cancer detection with an OR of 1.55 (95% CI 1.09 to 2.19). No significant association was observed between an extended biopsy technique and the detection of smaller (95% CI 0.39 to 1.21) or insignificant (95% CI 0.54 to 4.54) cancers. PSAD was the single parameter found to be independently associated with the detection of overall cancer and clinically insignificant cancer. PSAD greater than 0.1 had an OR of 1.63 (95% CI 1.37 to 1.94) for the detection of overall cancer. Moreover, it was also inversely associated with the detection
507
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
TABLE 3. Unadjusted associations between demographic and disease factors, and detection of cancer, clinically insignificant cancer and smaller cancers based on GPC % Overall Detection
p Value
% Clinically Insignificant Detection
p Value
% GPC 10% or Less*
No. subjects 740 136 317 Overall rate 44.5 12.6 32.8 Age older than 60 49.6 ⬍0.01 7.8 0.13 29.5 Black race 50.0 0.04 15.4 0.15 21.4 Prostate vol greater than 40 cc 33.4 ⬍0.01 24.2 0.07 30.6 PSAD greater than 0.1 ng/ml/cc 50.5 ⬍0.01 12.2 0.35 25.4 Biopsy indications: Abnormal DRE 44.6 0.53 9.1 0.74 20.0 Increased PSA 45.2 ⬍0.01 12.7 ⬎0.99 29.0 More than 1 indication 63.6 ⬍0.01 7.7 0.68 16.1 * Cutoff was chosen because 10% was 25th percentile of standard biopsy group and median value in insignificant cancer group.
p Value
0.07 0.75 0.78 0.02 0.15 0.79 0.10
FIG. 1. Unadjusted cancer detection rates detection for standard and extended biopsy techniques (overall and clinically insignificant cancer detection p ⫽ 0.113 and 0.29, respectively).
FIG. 3. Relationships between PSAD, and detection of prostate cancer overall and clinically insignificant cancers.
FIG. 2. GPC of standard and extended biopsy techniques (p ⫽ 0.14).
of insignificant disease with an OR of 0.44 (95% CI 0.20 to 0.98). Specifically at higher PSAD cancer was not only more likely to be detected, but it was also more likely to be significant disease (fig. 3). DISCUSSION
Our findings demonstrate that an extended pattern prostate biopsy technique significantly increases the likelihood of overall cancer detection at initial biopsy. Eskew et al also
advocated an extended pattern.14 They found a statistically significant advantage (35% greater detection) with the additional cores of a 5 region biopsy.9 On the other hand, comparisons of cancer detection rates using a 12 core schema vs sextant biopsy showed no such improvement. This may be due to the fact that these patients were part of a screening population, in contrast to being referred specifically for prostate biopsy. With their 11 site pattern technique Babaian et al detected 31% more cancers at initial biopsy compared with sextant biopsy, although this increase in cancer detection was not statistically significant.15 It should be noted that their template differed somewhat with additional cores obtained from the midline and transition zone, and 2 taken from the anterior horns. Interestingly the more recent results of this group demonstrated a significant increase in cancer detection using their 11 core scheme.16 However, the study population included patients undergoing initial and repeat prostate biopsy.
508
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY
An equally important finding was the lack of an association between an extended biopsy technique and the detection of smaller or clinically insignificant tumors. Although critics warn of the potential of finding insignificant disease, to date no one has been able to detect this phenomenon. Eskew et al compared the pathology results of prostatectomy specimens detected by their 5 region biopsy vs a sextant biopsy technique.17 They noted no significant difference in tumor volume, Gleason grade or tumor stage. Naughton et al assessed men who underwent more than 6 biopsies during 1 or more biopsy sessions.18 Their analyses did not detect any difference compared with the sextant group in terms of Gleason score, cancer volume and organ confinement of possibly harmless cancer (tumor volume less than 0.2 cc, Gleason score less 7 and no capsular penetration). Naya et al found no disparity in the incidence of extraprostatic extension of cancers detected with the sextant vs the extended template.16 Furthermore, the additional cores of the extended biopsy technique enhanced sensitivity for predicting extraprostatic extension. Our conclusions expand the studies of these groups by focusing on extended cores at initial biopsy and then defining small tumors based on GPC as well as the complete Epstein classification of insignificant tumors.13 The National Comprehensive Cancer Network Practice Guidelines for Prostate Cancer Early Detection suggest an extended pattern biopsy comprising sextant cores along with sampling of the lateral peripheral zone and lesions suspicious on palpation or imaging.11 Our findings support these practice guidelines and our current report provides evidence that an extended pattern technique increases overall cancer detection without any significant increase in detecting clinically insignificant disease. By increasing the likelihood of cancer detection at initial biopsy we decrease substantially the proportion of men with negative biopsies who then undergo repeat biopsy because of persistently increasing PSA or abnormal DRE. It has been demonstrated that abnormal PSA is associated with cancer worry. There are benefits that cannot be quantified, such as relieving the psychological stress of patients who are concerned about the false-negative rate inherent in the standard sextant technique. Our findings of the usefulness of PSAD are consistent with those in prior studies.13 At lower PSAD prostate cancer was less likely to be detected but a greater proportion of them were insignificant cancers. PSAD greater than 0.2 was the threshold at which there was a lower likelihood of detecting insignificant cancer. Using 40 gm as the average prostate size a PSA of 8 ng/ml results in a PSAD of 0.2 and according to our results there was an approximately 23% chance of insignificant cancer. However, at PSA 12 ng/ml and PSAD 0.3 one would expect only about 3% insignificant disease. Beyond PSAD greater than 0.3 all cancers detected were clinically significant. When counseling patients who are considering definitive therapy for prostate cancer, the simple calculation of PSAD may be useful for determining whether the cancer detected by extended biopsies is potentially insignificant disease. This study has several limitations. 1) We did not investigate adverse effects at prostate biopsy that were directly related to obtaining additional biopsy cores. Common complications of prostate biopsy range from gross hematuria, which occurs in 12.8% of patients, to hospitalization for infection in 0.2%.11 Naughton et al did not observe any difference in morbidity when taking 12 vs 6 cores.19 On the other hand, Rodriguez et al found that fevers and chills were related to the number of biopsies.20 However, all of these patients were treated with antibiotics on an outpatient basis and none progressed to infectious sequelae. 2) Our results were based on a retrospective observational study with the potential for confounding due to individual physician practices. The extended pattern group had a lower mean age, higher median prostate volume, lower median
PSAD and a higher percent of patients with increased PSA as an indication for biopsy. These factors may have impacted the finding of insignificant disease. Therefore, we attempted to overcome these limitations with adjusted multivariable models. Furthermore, our definition of clinically insignificant cancer is based on surgical pathology results. Men who elected radical prostatectomy for therapy differed from the study population as a whole in having a lower mean age, lower median prostate volume and higher PSAD, while there was a higher percent with increased PSA. Thus, they may not be generalizable to all men who undergo a biopsy. CONCLUSIONS
An extended pattern prostate biopsy technique increases the cancer detection rates without a significant increase in clinically insignificant disease. PSAD may identify patients in whom insignificant disease is uncommon. More research is necessary to determine the optimal prostate biopsy strategy to balance all risks and benefits. Dr. James E. Montie reviewed the manuscript. REFERENCES
1. Stephenson, R. A.: Prostate cancer trends in the era of prostatespecific antigen. An update of incidence, mortality, and clinical factors from the SEER database. Urol Clin North Am, 29: 173, 2002 2. Hu, J. C., Elkin, E. P., Pasta, D. J., Lubeck, D. P., Kattan, M. W., Carroll, P. R. et al: Predicting quality of life after radical prostatectomy: results from CaPSURE. J Urol, 171: 703, 2004 3. Walsh, P. C.: Radical prostatectomy for localized prostate cancer provides durable cancer control with excellent quality of life: a structured debate. J Urol, 163: 1802, 2000 4. Talcott, J. A., Rieker, P., Clark, J. A., Propert, K. J., Weeks, J. C., Beard, C. J. et al: Patient-reported symptoms after primary therapy for early prostate cancer: results of a prospective cohort study. J Clin Oncol, 16: 275, 1998 5. Hamilton, A. S., Stanford, J. L., Gilliland, F. D., Albertsen, P. C., Stephenson, R. A., Hoffman, R. M. et al: Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol, 19: 2517, 2001 6. Hodge, K. K., McNeal, J. E., Terris, M. K. and Stamey, T. A.: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol, 142: 71, 1989 7. Daneshgari, F., Taylor, G. D., Miller, G. J. and Crawford, E. D.: Computer simulation of the probability of detecting low volume carcinoma of the prostate with six random systematic core biopsies. Urology, 45: 604, 1995 8. Presti, J. C., Jr., Chang, J. J., Bhargava, V. and Shinohara, K.: The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol, 163: 163, 2000 9. 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 10. Talcott, J. A.: New era in prostate-cancer care: what we know and what we don’t. Lancet Oncol, 4: 204, 2003 11. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Available at www.nccn.org. Accessed June 2004 12. Nelson, C. P., Rubin, M. A., Strawderman, M., Montie, J. E. and Sanda, M. G.: Preoperative parameters for predicting early prostate cancer recurrence after radical prostatectomy. Urology, 59: 740, 2002 13. Epstein, J. I., Walsh, P. C., Carmichael, M. and Brendler, C. B.: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA, 271: 368, 1994 14. Naughton, C. K., Miller, D. C., Mager, D. E., Ornstein, D. K. and Catalona, W. J.: A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol, 164: 388, 2000 15. Babaian, R. J., Toi, A., Kamoi, K., Troncoso, P., Sweet, J., Evans, R. et al: A comparative analysis of sextant and an extended
EXTENDED PATTERN TECHNIQUE FOR INITIAL PROSTATE BIOPSY 11-core multisite directed biopsy strategy. J Urol, 163: 152, 2000 16. Naya, Y., Ochiai, A., Troncoso, P. and Babaian, R. J.: A comparison of extended biopsy and sextant biopsy schemes for predicting the pathological stage of prostate cancer. J Urol, 171: 2203, 2004 17. Eskew, L. A., Woodruff, R. D., Bare, R. L. and McCullough, D. L.: Prostate cancer diagnosed by the 5 region biopsy method is significant disease. J Urol, 160: 794, 1998 18. Naughton, C. K., Smith, D. S., Humphrey, P. A., Catalona, W. J. and Keetch, D. W.: Clinical and pathologic tumor
509
characteristics of prostate cancer as a function of the number of biopsy cores: a retrospective study. Urology, 52: 808, 1998 19. Naughton, C. K., Ornstein, D. K., Smith, D. S. and Catalona, W. J.: Pain and morbidity of transrectal ultrasound guided prostate biopsy: a prospective randomized trial of 6 versus 12 cores. J Urol, 163: 168, 2000 20. Rodriguez, L. V. and Terris, M. K.: Risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. J Urol, 160: 2115, 1998