|Subject:||Prostate Saturation Biopsy|
|Policy #:||SURG.00107||Current Effective Date:||06/28/2016|
|Status:||Reviewed||Last Review Date:||05/05/2016|
This document addresses prostate saturation biopsy, also called prostate saturation needle biopsy, which involves taking numerous samples of prostate tissue in order to increase the likelihood of detecting prostate cancer in a subgroup of high-risk individuals in whom previous conventional prostate biopsies have been negative.
Note: Please see the following related documents for additional information:
Investigational and Not Medically Necessary:
Transrectal ultrasound-guided prostate saturation biopsy is considered investigational and not medically necessary.
Transperineal stereotactic template-guided prostate saturation biopsy is considered investigational and not medically necessary.
Prostate biopsy commonly occurs based on detection of elevated prostate-specific antigen (PSA) performed as part of prostate cancer screening. Typically, the initial biopsy consists of a small number of core specimens taken of the prostate. Individuals with an elevated PSA level but with a normal initial biopsy often undergo repeat biopsy evaluation. In addition, some advocate more extensive biopsy procedures in an individual with low grade prostate cancer to verify the result. Based on concerns about false-negative biopsies and misclassification as low grade, prostate saturation biopsy, an approach with an increase in the total number of biopsy specimens, was developed.
An American Urological Association (AUA, 2013) guideline states that early detection of prostate cancer is driven by PSA-based screening followed by prostate biopsy for diagnostic confirmation. The AUA Panel recommends:
…that the urologist should consider factors that lead to an increased PSA including prostate volume, age, and inflammation rather than using an absolute level to determine the need for a prostate biopsy - keeping in mind that PSA is not a dichotomous test but rather a test that indicates the risk of a harmful cancer over a continuum. The Panel believes that postponing and/or avoiding a prostate biopsy 1) in a man with a large prostate, 2) in the older male especially if in less than excellent health, and 3) in the setting of a suspicion of prostatic inflammation, would be acceptable even at PSA levels exceeding 3-4ng/mL.
In 2015, an updated AUA white paper, AUA/Optimal Techniques of Prostate Biopsy and Specimen Handling, includes the following recommendations for prostate biopsy:
As the number of cores increases, the diagnostic yield becomes more marginal. Only limited evidence supports the use of initial biopsy schemes involving more than 12 cores or saturation... The differences in populations studied makes comparing the results from the studies of protocols involving different numbers of cores challenging. Patient age, serum PSA, ethnicity, and family history all influence cancer detection rate (CDR) for any biopsy strategy. What can be concluded from the literature is that increasing core number increases CDR and sextant biopsy results in an unacceptably high likelihood of false-negative results, leading to under detection of clinically significant cancers. Increasing core numbers using saturation techniques might identify cancers missed on extended core sampling but this strategy also increases the risk of over detection of indolent cancers without significantly improving CDR or pathology concordance.
The use of saturation biopsy protocols has been evaluated as an initial biopsy technique, in individuals with repeated/prior negative biopsies or high-grade prostatic intraepithelial neoplasia, and in individuals prior to or being followed on active surveillance protocols. The following rationale reviews the proposed clinical utility of a saturation biopsy approach for each clinical scenario.
Initial Prostate Biopsy
The National Comprehensive Cancer Network® (NCCN®, 2016) Clinical Practice Guideline (CPG) for prostate cancer early detection recommends a systematic prostate biopsy approach performed under TRUS guidance for individuals undergoing initial prostate biopsy. A commonly used scheme for prostate biopsy is the 12-core extended-pattern biopsy scheme that includes a standard sextant as well as a lateral sextant scheme. A number of studies have compared the diagnostic yield of finding prostate cancer and have not found that use of saturation biopsy improves cancer detection rates compared with extended biopsy strategies (Jones, 2006; Sur, 2004). Authors suggest that large, easy-to-identify tumors in the general population are usually identified without a need for saturation biopsy. Ashley and colleagues (2008) performed a nonrandomized cohort study (n=469) of a consecutive series of prostate biopsies to determine whether saturation biopsy (greater than or equal to 24 cores) detects more prostate cancer than a standard 12-18 core office biopsy technique. The primary outcome assessed was the detection of prostate cancer. After adjustments for covariates, saturation biopsy did not detect more prostate cancer than the control group (odds ratio [OR], 1.2; p=0.339). The investigators concluded that saturation biopsy did not appear to detect more abnormal prostate pathology than standard office biopsy of the prostate, and the procedure may be associated with increased cost and morbidity.
Lane and colleagues (2008) studied the use of prostate saturation biopsy as an initial biopsy strategy in 257 men between January 2002 and April 2006. Prostate cancer was initially detected in 43% of the participants who underwent saturation biopsy. In the 147 men with negative initial saturation biopsy, follow-up including DRE and repeat PSA measurement was recommended at least annually. Persistently increased PSA or an increase in PSA was seen as an indication for repeat saturation biopsy. During the median follow-up of 3.2 years after negative initial saturation biopsy, 121 men (82%) underwent subsequent evaluation with PSA and DRE. Median PSA remained 4.0 ng/ml or greater in 57% of the men and it increased by 1 ng/ml or greater in 23%. Prostate cancer was detected in 14 of 59 men (24%) undergoing repeat prostate biopsy for persistent clinical suspicion of prostate cancer. No significant association was demonstrated between prostate cancer detection and initial or follow-up PSA, or findings of atypia and high grade prostatic intraepithelial neoplasia on initial saturation biopsy. Cancers detected on repeat prostate biopsy were more likely to be a Gleason score "6" and organ confined at prostatectomy than were those diagnosed on initial saturation biopsy. The investigators concluded that while office based saturation prostate biopsy may improve cancer detection in men who have previously undergone a negative prostate biopsy; it does not improve cancer detection as an initial biopsy technique.
Chun and colleagues (2011) conducted a systematic review of the current peer-reviewed literature regarding the performance and interpretation of initial prostate biopsy strategies. The authors stated the evidence demonstrates that a minimum of 10 but not greater than 18 systematic cores, with 14 to 18 cores taken in glands ≥ 50 cm3, is recommended on initial prostate biopsy.
Li and colleagues (2014) performed a retrospective, nonrandomized cohort study of 438 men who had an initial saturation biopsy and 3338 men who had an initial extended prostate biopsy. In an analysis stratified by PSA values, there was a statistically significantly higher rate of prostate cancer detection using a saturation biopsy strategy in men with a PSA less than 10 ng/mL. Detection rates among men with PSA < 4 ng/mL were 47% with saturation biopsy (40 of 85) and 33% with extended biopsy (288 of 878; p=0.008). Rates among men with PSA between 4 and 9.9 ng/mL were 51% with saturation biopsy (144 of 283) and 43% with extended biopsy (867 of 2022; p=0.011). There was not a statistically significant difference in detection rates between groups when PSA was > 10 ng/mL. Detection rates in men with PSA > 10 mg/mL were 60% with saturation biopsy (42 of 67) and 61% with extended biopsy (267 of 438; p=0.879). Limitations of this study include the retrospective design, potential for selection bias as the biopsy protocol was determined by the attending urologist, and lack of homogeneous biopsy schemes in each group based on technical performance.
Jiang and colleagues (2013) published a systematic review and meta-analysis of studies evaluating the utility of an initial transrectal saturation biopsy compared to an extended biopsy strategy. Eight studies with 11,997 participants who underwent TRUS-guided biopsies for the first time and met other eligibility criteria were included in the analysis. Two of the studies were randomized controlled trials, one study used a prospective paired design, and five were nonrandomized controlled studies. Prostate cancer was diagnosed in 42% (2328 of 5486) of participants who underwent saturation biopsy, compared to 39% (2562 of 6511) of men who had extended biopsy. The detection rate was statistically significantly higher in the saturation biopsy group (risk difference [RD] 0.004; 95% confidence interval [CI], 0.01 to 0.008; p=0.002). When only the higher quality studies (n=3) were included in the meta-analysis, the two randomized controlled trials and prospective paired design, the detection rate was statistically significantly higher with saturation biopsy (RD 0.03, 95% CI, 0.01 to 0.05; p=0.01). For the analysis limited to higher quality studies, the authors did not report the proportion of men in each group diagnosed with prostate cancer. Although the authors found statistically significantly higher rates of diagnosis in their overall pooled analyses, the degree of difference in diagnosis rates may not be clinically significant. In a subgroup analysis, in individuals with PSA less than 10 ng/mL, prostate cancer was diagnosed in 998 of 2597 men (38%) in the saturation biopsy group and 1135 of 3322 men (34%) in the extended biopsy group. The diagnosis rate was significantly higher in men receiving the saturation biopsy protocol (RD 0.04; 95% CI, 0.01 to 0.07; p=0.002). As in the overall analysis, the clinical significance of this degree of difference is unclear. There was not a statistically significant difference between groups in the diagnostic yield for men with PSA > 10 ng/mL (RD 0.03; 95% CI, -0.01 to 0.08; p=0.15).
In summary, whether the increased detection rate by more extensive saturation biopsy is due to the additional biopsy cores or the location from which the cores are taken is still unknown. The AUA/Optimal Techniques of Prostate Biopsy and Specimen Handling white paper (2015) on saturation biopsy performed using the transrectal approach concludes that "…the results of biopsy schemes involving more than 12 cores or saturation biopsies appear to have a higher concordance rate with results from prostatectomy, but they also appear to increase the rate of insignificant cancer detection." A potential disadvantage of an initial saturation biopsy strategy is that taking an increased number of cores could escalate the risk of detection of clinically insignificant cancer and lead to overdiagnosis and overtreatment. While the data suggests an increase in the rate of diagnosis of prostate cancer using saturation techniques, there is no peer-reviewed literature which conclusively demonstrates that this approach results in reduced mortality or other clinically significant outcomes when compared to standard biopsy protocols.
Repeat Prostate Biopsy
The peer-reviewed literature evaluating repeat prostate biopsy strategies consists of a systematic review and prospective and retrospective studies. Some studies compare extended-biopsy to saturation biopsy schemes, while others compare saturation biopsy as a primary or repeat prostate biopsy technique (Pepe and Aragona, 2007).
Stewart and colleagues (2001) conducted a retrospective, comparative study suggesting that markedly increasing the number of cores obtained during prostate needle biopsy may improve the cancer detection rate in men with persistent indications for repeat biopsy. An average of 23 saturation biopsy cores (range 14 to 45) were distributed throughout the entire prostate, including the peripheral, medial and anterior regions. The investigators reported that cancer was detected in 34% (77 of 224) of the participants. The overall complication rate for saturation biopsy was 12%; hematuria requiring hospital admission was the most common adverse event. The investigators reported the evidence suggests that the sensitivity of needle biopsy could improve by 30% to 35% when increasing the number of biopsy cores beyond six (that is, 14-45 cores). The extent to which an increase in detection rate would reduce morbidity and mortality from prostate cancer or increase the percentage of men treated unnecessarily was unknown.
Eichler and colleagues (2006) systematically reviewed and compared the cancer detection rates and complications of different extended prostate biopsy methods. The reviewers included studies that compared different systematic prostate biopsy methods using sequential sampling or a randomized design in men scheduled for biopsy due to suspected prostate cancer. Pooled data from 68 studies compared a total of 94 extended schemes with the standard sextant scheme; 87 studies were analyzed with a total of 20,698 participants. The studies included participants from all age groups with suspected prostate cancer scheduled for prostate biopsy with increased PSA, a positive DRE, or both. The authors concluded that prostate biopsy schemes consisting of 12 cores that add laterally directed cores to the standard sextant scheme "strike the balance" between the cancer detection rate and adverse events; taking more than 12 cores added no significant benefit.
Simon and colleagues (2008) reported on the results using an extensive saturation biopsy in 40 men with a clinical suspicion of prostate cancer after previous negative prostate biopsies. The median (range) number of cores taken was 64 (39-139) and was adjusted to the size of the prostate. Of the 40 men, 18 (45%) had cancer in at least 1 core. A total of 16 men had marked hematuria after the biopsy procedure. The investigators concluded there was no significant increase in the cancer detection rate in an extensive saturation biopsy regimen compared to published series with fewer cores, but there was an increased morbidity.
Stav and colleagues (2008) evaluated the diagnostic value of prostate saturation biopsy in men (n=27) with a PSA greater than 10 ng/mL, PSA velocity greater than 0.75 ng/mL/year, free PSA ratio < 0.2, and at least three sets of negative biopsy specimens. According to the investigators' findings, prostate saturation biopsy has a low diagnostic yield in men who previously had at least three sets of negative traditional biopsy specimens. In all the cases where prostate cancer was found, the histologic features were consistent with biologically insignificant disease.
Zaytoun and colleagues (2011) conducted a nonrandomized, prospective comparative study of extended biopsy versus office-based transrectal saturation biopsy in a repeat biopsy population. After an initial negative biopsy, 1056 men underwent either a repeat 12- to 14-core biopsy (n=393) or a 20- to 24-core repeat biopsy (n=663) at the discretion of the attending urologist's practice pattern. Indications for second biopsy included a previous suspicious pathologic finding and/or clinical indications such as abnormal digital rectal examination, persistently increased PSA, and PSA (increasing) > 0.75 ng/mL annually. Prostate cancer was detected in 29.8% (n=315) of repeat biopsies. The saturation biopsy group had a detection rate of 32.7% versus 24.9% in the extended biopsy group (p=0.0075). Of the 315 positive biopsies, 119 (37.8%) revealed clinically insignificant cancer (defined as Gleason sum > 7, a total of 3 fewer positive cores, and a maximum of 50% or less of cancer in any positive core). There was a trend toward increased detection of clinically insignificant cancer detection in the saturation versus the extended biopsy cases, 40.1% versus 32.6%, respectively (p=0.02).
Giulianelli and colleagues (2011) evaluated whether or not the saturation biopsy technique after a first negative biopsy increased the cancer detection rate in men with a PSA less than 10 ng/mL. From January 2004 to January 2006, 780 men underwent TRUS-guided prostate biopsies. Of these men, 186 (23.8%) were diagnosed with prostate cancer, while 594 (76.2%) had negative biopsies. For 1 year, all of the men with no evidence of cancer were observed according to a follow-up schedule including PSA every 3 months and DRE every 6 months. During this period, 140 men showed an increase of PSA (<10 ng/mL) or a low PSA free/total. This group underwent a second TRUS-guided prostate biopsy with the saturation technique under general anesthesia. Of the 140 men, 50 (35.7%) had prostate cancer showing a Gleason score < 7 (14 men, 28%), Gleason score of 7 (32 men, 64%), or Gleason score of 8 to 10 (4 men, 8%). Apical biopsies carried out in the anterior horn of peripheral zone tissue showed cancer in 35 men (70% of those rebiopsied), versus 24% in lateral zones, and 5% for parasagittal. In the men who underwent the saturation biopsy, cancer was considered clinically significant (defined as positive biopsy cores of > 3) in 47 men (94%). A total of 48 of 50 men underwent a radical prostatectomy and 2 men underwent external beam radiation therapy. The authors concluded that the saturation biopsy technique increased the cancer detection rate by 36% in men with a PSA < 10 ng/mL, after a first negative biopsy, and showed a higher positivity (70% prostate cancer detection rate) if the saturation biopsy included the anterior horn of peripheral zone tissue. It is important to note however, that the size of the prostate may help to explain why the cancer detection rate was increased on repeat biopsy using the saturation technique. As in an earlier study, the authors observed a higher cancer detection rate on rebiopsy in men with larger prostate volumes (63.3 ± 15.2 cc) when utilizing the saturation technique.
Scattoni and colleagues (2014) performed an analysis of the peer-reviewed literature to identify the optimal approach for a repeat prostate biopsy scheme. The authors state the recommended approach in a repeat biopsy setting is a 12-core, extended scheme biopsy technique; a sampling with more than 12 cores may optimize cancer detection in individuals with specific clinical characteristics. A saturation biopsy strategy of 20 or greater cores "…clearly improves cancer detection if clinical suspicion persists after previous negative biopsy." However, "…international guidelines do not strongly recommend a saturation biopsy in all situations of repeated setting." At present, an extended prostate biopsy "is still the gold standard" even if saturation biopsy seems to be necessary in many cases.
The current NCCN CPG for prostate cancer early detection (2016) recommends "repeat prostate biopsy, based on risk" for management of benign biopsy results (after initial biopsy), stating, "It is well known that a negative biopsy does not preclude a diagnosis of prostate cancer on subsequent biopsy. Those patients with negative prostate biopsies should be followed with DRE and PSA. Repeat prostate biopsy is based on risk." A saturation biopsy strategy is not included in the algorithm pathway; however, a footnote states:
Emerging evidence suggests that use of multiparametric MRI and/or use of refined prostate biopsy techniques (image guidance using MRI/ultrasound fusion, transperineal, or saturation prostate biopsies) may be of value. These techniques may help identify regions of cancer missed on prior prostate biopsies and should be considered in selected cases after at least 1 negative prostate biopsy.
The "emerging evidence" discussed by the NCCN guideline includes a nonrandomized, prospective comparative study of extended biopsy versus office-based transrectal saturation biopsy in a repeat biopsy population (Zaytoun, 2011), and a study by Merrick and colleagues (2007) that attempted to establish the incidence of prostate cancer, anatomic distribution, Gleason score profile, and tumor burden in men (n=102) diagnosed by a transperineal template-guided saturation biopsy (TTSB) technique.
While the data suggests an increase in the rate of diagnosis of prostate cancer using saturation techniques in individuals undergoing repeat prostate biopsy, there is no peer-reviewed literature which conclusively demonstrates that this approach results in reduced mortality or other clinically significant outcomes when compared to standard biopsy protocols.
High-grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP)
HGPIN and ASAP are non-malignant but pathologically atypical findings on a prostate biopsy. In the non-randomized cohort study by Ashley and colleagues (2008), the authors evaluated whether saturation biopsy (n=168) detected more HGPIN and ASAP than a standard 12- to 18-core office biopsy technique (n=301). Subjects in the saturation biopsy cohort carried a more frequent diagnosis of HGPIN or ASAP. After adjusting for covariates, saturation biopsy did not detect more abnormal pathology than a standard office prostate biopsy technique (HGPIN [OR 1.4; p=0.368], or ASAP [OR 2.2; p=0.201]).
Lee and colleagues (2011) evaluated the role of transrectal saturation biopsy for cancer detection in men with HGPIN diagnosed by extended biopsy. From 1999 to 2009, 314 men had at least one or more repeat biopsies due to the presence of exclusive HGPIN (without any other pathologic finding) in a previous extended biopsy. They were divided into two groups according to the initial follow-up biopsy scheme; 178 men were followed using a second standard extended biopsy scheme and 136 men were followed up using the saturation biopsy scheme. In the standard repeat biopsy group, 35 of 178 (19.7%) men had cancer on initial repeat biopsy. In the saturation biopsy group, 42 of 136 (30.9%) had cancer on initial repeat biopsy (overall, p=0.04). Multivariate analysis demonstrated that the biopsy scheme on repeat biopsy was an independent predictor of prostate cancer detection (OR 1.85; 95% CI, 1.03, 3.29), exclusive of age, PSA level, days from initial biopsy, DRE status, and multifocal prostatic epithelial neoplasia (PIN). Pathologic findings on repeat biopsies demonstrated similar Gleason grades, regardless of biopsy technique: Gleason 6 was present in 74.3% and 73.1% of specimens in the standard and saturation schemes, respectively. The presence of a Gleason score of 8 or higher was 8.6% and 9.5%, respectively. Limitations of this study include its retrospective design, exclusion of family history information for multivariate analysis (as it is a known risk factor), and that the diagnoses of HGPIN was not retrospectively reviewed and confirmed by a single, blinded pathologist. Additional prospective studies of men with multifocal HGPIN alone and randomly designed saturation versus standard biopsy are needed to determine if saturation biopsy enhances the detection of clinically significant prostate cancer in men initially diagnosed with HGPIN.
The current NCCN CPG for prostate cancer early detection (2016) recommends a repeat biopsy, based on risk, for management of biopsy results (initial) that are benign or focal HGPIN, stating "it is well known that a negative biopsy does not preclude a diagnosis of prostate cancer on subsequent biopsy. Those patients with negative prostate biopsies should be followed with DRE and PSA." A saturation biopsy strategy is not included in the algorithm pathway; however, a footnote states:
Emerging evidence suggests that use of multiparametric MRI and/or use of refined prostate biopsy techniques (image guidance using MRI/ultrasound fusion, transperineal, or saturation prostate biopsies) may be of value. These techniques may help identify regions of cancer missed on prior prostate biopsies and should be considered in selected cases after at least 1 negative prostate biopsy.
The "emerging evidence" discussed by the NCCN guideline includes a nonrandomized, prospective comparative study of extended biopsy versus office-based transrectal saturation biopsy in a repeat biopsy population (Zaytoun, 2011), and a study by Merrick and colleagues (2007) that attempted to establish the incidence of prostate cancer, anatomic distribution, Gleason score profile, and tumor burden in men (n=102) diagnosed by a TTSB technique.
For management of biopsy results for multifocal HGPIN (> 2 sites), the NCCN guideline recommends using "...an extended pattern rebiopsy (within 6 months) with increased sampling of the affected site and adjacent areas. If no cancer is found, close follow-up with PSA and DRE is recommended at 1 year intervals initially" (NCCN 2016). The repeat biopsy algorithm does not include a saturation biopsy strategy in the management of multifocal HGPIN or ASAP (NCCN, 2016).
A saturation biopsy protocol has been suggested as a part of active surveillance in individuals with clinically localized prostate cancer, in terms of being able to more accurately assess tumor volume, tumor grade, or both. The peer-reviewed literature is limited in studies that evaluate the use of a saturation biopsy protocol for active surveillance (Ayres, 2012).
Linder and colleagues (2013) reviewed data on 500 consecutive individuals who underwent TRUS-guided biopsy by a standard template (12 cores) or saturation template (≥ 18 cores, median 27 cores) with subsequent radical prostatectomy. The authors examined the ability of standard and saturation transrectal prostate biopsy techniques to predict appropriate candidates for active surveillance. A total of 218 individuals were identified who were potential candidates for active surveillance using the criteria of Gleason score of no > 6, clinical stage T1 or T2a, PSA < 10 ng/mL, and involvement of no more than 33% of cores. A standard biopsy was performed in 124 individuals and saturation biopsy in 94 individuals. In a multivariate analysis, the biopsy method was not a significant predictor of upstaging on analysis of pathological findings (p=0.26). The 5-year biochemical failure-free survival estimates, defined as PSA at least 0.4 ng/mL, were not significantly different in the standard biopsy group compared to the saturation biopsy group, 97% versus 95% (p=0.11), respectively. A conclusion drawn from this review is that in men with prostate cancer, standard and saturation transrectal prostate biopsies techniques may be equally predictive of candidates for active surveillance.
The AUA's guidelines for the management of clinically localized prostate cancer states an ideal regimen for active surveillance has not been defined but could include periodic repeat prostate biopsies to assess for sampling error of the initial biopsy as well as for subsequent progression of tumor grade and/or volume (AUA, 2011). The NCCN CPG for prostate cancer includes recommendations for prostate biopsy at specific intervals. For active surveillance and observation for individuals with clinically localized prostate cancers who are candidates for definitive treatment, follow-up should include:
A saturation biopsy scheme is not included as part of an active surveillance protocol (NCCN, 2016).
Transperineal Saturation and Three-Dimensional Mapping Biopsy Techniques
An alternative to a transrectal saturation biopsy is a transperineal prostate biopsy technique performed under local, regional, or general anesthesia using a brachytherapy grid and transrectal ultrasound guidance.
The NCCN CPG for prostate cancer early surveillance (2016) states:
...there is interest in saturation approaches to biopsy (often image-guided) to improve diagnostic accuracy. However, at present the panel does not recommend routine use of transperineal biopsy for initial biopsy, although it can be considered in repeat biopsy setting...The transperineal approach may have a lower risk of infection, may allow for better saturation of the gland, and may be more acceptable to patients compared with the transrectal approach (Acher, 2013).
Another possible benefit of transperineal versus transrectal approach may be more accurate staging; however, "...the transperineal approach may be associated with a higher rate of urinary retention" (NCCN, 2016).
Merrick and colleagues (2007) established the incidence of prostate cancer, anatomic distribution, Gleason score profile, and tumor burden in men (n=102) diagnosed by a TTSB technique. All but 1 participant in this study had a minimum of one prior negative TRUS biopsy. In multivariate analysis, prostate volume was the best predictor for prostate cancer diagnosis. The authors concluded that TTSB diagnosed prostate cancer in 42.2% of participants; however, considerable anatomic variability in prostate cancer distribution was documented in the study results. Additional study is required to determine appropriate candidates for TTSB and the number of biopsy cores and regions to be sampled.
Barqawi and colleagues (2011) prospectively studied the use of a 3-dimensional mapping biopsy (3DMB) technique (n=215) on 180 men with early stage, organ confined prostate cancer based on TRUS-guided 10- to 12-core biopsies, and on 35 men with prior negative TRUS biopsies. The purpose of the study was to determine the impact of this grid-based 3DMB technique on decision making for primary management of early stage prostate cancer. Eligible participants presented with a histological diagnosis of prostate cancer (Gleason 7 or less) on prior TRUS-guided biopsy and were considering active surveillance or targeted focal therapy. At presentation the median PSA was 4.8 ng/ml (range, 0.5 to 72.4) and median prostate volume was 35 cc (range, 9 to 95). The 35 participants with prior negative TRUS-guided biopsies were also offered 3DMB and analyzed separately. The median number of cores acquired by 3DMB was 56 (range, 8 to 124), and the median number of positive cores was 2 (range, 0 to 19). Of men with positive TRUS biopsies, 144 (80%) had positive 3DMB. Of the 180 participants, Gleason score upgrade was documented in 49 (27.2%) of the participants with up-stage occurring in 82 (45.6%) of the participants; 36 (20.0%) of the participants had negative 3DMB. Comparison of Gleason grades between 3DMB and previous TRUS-guided biopsy showed that 48.9% remained unchanged. Only 16.1% of 3DMB results, based on Gleason grade and stage, matched positive TRUS-guided biopsy results. The incidence of urinary retention catheter requirement of greater than 48 hours was 3.2% and the incidence of transient orthostatic hypotension was 5%. There were no documented urinary tract infections. After 3DMB, 38 participants elected radical prostatectomy, 11 received radiation therapy, 45 underwent whole gland cryotherapy, 60 were enrolled in a targeted focal cryotherapy clinical study and 44 elected active surveillance. One participant elected high intensity focused ultrasound as part of another investigational study and 4 underwent targeted focal interstitial laser therapy. Post mapping data including treatment choices after 3DMB were not available for analysis on 12 participants. The investigators concluded that for select individuals, these results demonstrate the potential for 3DMB to supplement available data when making a decision on treatment options for men with previously diagnosed prostate cancer; however, further study is warranted to determine the treatment effect of 5a-reductase inhibitors to decrease the rate of upgrade/upstage from TRUS guided biopsy, and the impact this has on the sensitivity of 3DMB to detect prostate cancer. Limitations of this study include the potential for interobserver bias, as the TRUS biopsies were read by various community pathologists. Clinician preference and referral patterns along with the anxiety level of those individuals with a negative TRUS biopsy may have influenced those men who subsequently underwent a 3DMB procedure. There was also no correlation with whole mount pathological specimens to determine whether the additional lesions detected were significant or insignificant and whether these findings truly reflected overall pathological findings. Finally, this study did not determine the effect of further disease staging on clinical outcome.
Addollah and colleagues (2011) compared a transrectal to transperineal approach using a saturation biopsy technique. A total of 472 men were evaluated; 70% (332) underwent a transrectal biopsy and 30% (140) underwent a transperineal biopsy with a 24-core prostate rebiopsy technique. Matching 280 participants with homogeneous characteristics representing the final study cohort, the authors reported an overall prostate cancer detection rate of 28.6%. There was no statistically significant difference in the prostate cancer detection rate between the transrectal and transperineal approach (31.4% vs. 25.7%, respectively; p=0.3). The type of approach was not an independent predictor of prostate cancer detection rate at multivariable analyses (OR 0.61; p=0.1).
Mabjeesh and colleagues (2012) reported on a cohort of high-risk men with at least two previous negative transrectal biopsies who then underwent a multiple-core prostate TTSB. Prostate cancer was detected in 26% of the 92 men, predominantly in the anterior zones. A median of 30 cores was taken in the saturation biopsies. Gleason score of ≥ 7 was detected in 46% of the diagnosed men. Most of the tumors (83.3%) were found in the anterior zones of the gland, with a significantly higher number of positive cores versus the posterior zones (mean, 4.9 vs. 1.5; p=0.015). Limitations of this study include the lack of any randomization and comparison with other biopsy approaches; therefore, the study contains biases regarding participant selection data (for example, prostate volume and age of participants). In addition, the size of the cohort studied limits extrapolating the results to the general population.
Ekwueme and colleagues (2013) prospectively evaluated 270 individuals from a single institution with persistent clinical suspicion of prostate cancer despite a median range of two sets of negative TRUS-guided biopsies. All participants who either had progression of PSA while on surveillance after a negative TRUS-guided biopsy (n=238), an elevated PSA level with family history of prostate cancer (n=15), and extensive HGPIN (n=13) or ASAP (n=4) underwent general anesthesia with a modified TTSB technique to collect a mean (range) of 28 (16 to 43) cores. The cohort included 51 participants with prostatic volume > 60 mL who were on daily medication for 3 to 6 months to reduce prostate size. The median (range) participant age was 64 (43 to 85) years, with a median (range) PSA of 10 (1 to 114) ng/mL and median (range) prostate volume of 45 (17-106) mL. Biopsy specimens were evaluated by a single pathologist. Prostate cancer was diagnosed in 55% (Gleason scores 6 in 28%, 7 in 43%, 8-10 in 29%) of participants. Cancer involvement was identified uniquely in the anterior region in 31 individuals (21%), in the middle third in 10 individuals (7%) and in the posterior region in 13 individuals (9%), although in 75% (111 of 148) of tumor positive cases there was some anterior involvement. There was no significant difference between the number of positive cores (2 vs. 1, p=0.091), maximum percentage core involvement (30% vs. 17.5%; p=0.315) and maximum tumor length (3.5 mm vs. 2 mm; p=0.092). A total of 14 individuals (5%) developed acute urinary retention.
The NCCN CPG for prostate cancer early detection (2016) discusses the use of TTSB and cites a number of studies that report similar rates of detection using saturation biopsies in men with previous negative biopsies (Merrick, 2007; Taira, 2010; Vyas, 2013); however, the NCCN guideline algorithm for management of biopsy results does not include a pathway recommending use of TTSB. In addition, the transperineal biopsy approach "may be associated with a higher rate of urinary retention" (NCCN, 2016).
Despite reporting a higher cancer yield in individuals with previously negative histology but suspicion of prostate cancer, use of a modified TTSB technique has its limitations, including risks inherent with general anesthesia and the potential for higher rates of acute urinary retention. Additional prospective randomized study is needed with direct comparison of the modified TTSB technique to other biopsy approaches, including a comparison to radical prostatectomy whole specimen, to validate mapping by this technique.
Ayres and colleagues (2012) evaluated the role of transperineal template prostate biopsies in 101 men on active surveillance for prostate cancer. The criteria for active surveillance included men ages 75 years or younger, Gleason score of ≤ 3+3, PSA ≤ 15 ng/mL, clinical stage T1-2a, and ≤ 50% TRUS-guided biopsy cores positive for cancer, with ≤ 10 mm of disease in a single core. The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed. The role of PSA and PSA kinetics were studied. In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies. Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under-sampled by transrectal biopsies. In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance, 38% had more significant disease. There was no correlation with PSA velocity or PSA doubling time. In total, 33% of men stopped active surveillance and had radical treatment. The study concluded that around one-third of men have more significant prostate cancer on transperineal template biopsies; however, this probably reflects under-sampling by initial transrectal biopsies rather than disease progression within 6 months of starting active surveillance.
Bittner and colleagues (2013) retrospectively analyzed cases of 485 individuals selected from a single-institution database to determine the incidence of prostate cancer and pathological grade and location of prostate cancer detected on a transperineal template guided mapping biopsy (TTMB) performed within 3 to 6 months of the most recent negative TRUS-guided biopsy. The incidence of individuals with 1, 2, or 3 or greater previous TRUS-guided biopsies was 55%, 26% and 19%, respectively. TTMB was performed in 75% of individuals for increasing or occasionally persistently increased PSA, in 19% for ASAP, and in 6% for HGPIN. All biopsy specimens were reviewed by a single pathologist with expertise in urology pathology. Prostate cancer was classified as clinically insignificant when all of certain criteria were met, including no core with Gleason score > 6, no core with > 50% involvement, PSA density < 0.15 ng/ml/ml and fewer than 3 cores containing cancer. Data was analyzed using the Pearson chi-square test applied to study population clinical, TTMB and cancer detection parameters to determine the significance of differences between the various TRUS biopsy cohorts. A median of 59 cores was submitted by TTMB technique for the entire study population. Cancer was detected in 226 individuals (47%) using the TTMB technique, including 196 (87%) individuals with clinically significant disease according to Epstein criteria. The proportion of Gleason 8-10 disease was highest among individuals with 3 or more previous TRUS-guided biopsies. The most common cancer detection site on TTMB was the anterior apex (152 of 226, 67%). Limitations of this study include the retrospective design with data evaluated from a single institution. In addition, the TTMB approach has drawbacks, including a relatively high rate of urinary retention and the need for general anesthesia which carries specific risks. A prospective randomized trial is needed comparing saturation to 12- to 14-core TRUS-guided biopsies involving extra anterior apical biopsy to TTMB in individuals with prior negative biopsies to determine if TTMB can reduce mortality or other clinically significant outcomes when compared to standard biopsy protocols for individuals who are candidates for active surveillance.
The National Institute for Health and Clinical Excellence (NICE, 2010) interventional procedure guidance on transperineal template biopsy and mapping of the prostate states:
…Current evidence on the efficacy of transperineal template biopsy of the prostate shows an increase in diagnostic yield in patients with suspected prostate cancer who have had negative or equivocal results from other biopsy methods...Evidence was not found to support the use of transperineal template biopsy of the prostate as a mapping technique to determine the exact location and extent of prostate cancer in order to guide focal therapy, nor as part of an active surveillance regime.
The role of prostate saturation biopsy in the detection of prostate cancer requires further study. The evidence in the peer-reviewed published literature indicates that as an initial biopsy technique, the greater number of cores taken during a saturation biopsy does not improve initial cancer detection. There is also insufficient evidence in the peer-reviewed published literature in the form of randomized controlled trials to determine the clinical utility of prostate saturation biopsy, or that it improves health outcomes as a more effective biopsy technique when compared to an extended prostate biopsy for the detection of clinically significant prostate cancer. Despite the conclusions by some investigators that prostate saturation biopsy may provide increased accuracy in the predictability of prostate tumor volume and grade to select suitable candidates for active surveillance, it is unclear whether early detection and subsequent earlier treatment leads to any change in the natural history and outcome of individuals with prostate cancer. The evidenced-based guidelines for the evaluation of high-risk individuals in whom prior conventional prostate biopsies have been negative lacks consensus regarding which zones of the prostate to sample during the saturation biopsy and how many cores to obtain. The lack of specific algorithms for use of the prostate saturation biopsy technique may increase the risk of detecting clinically insignificant cancers which may lead to unnecessary treatment.
Prostate cancer is the most common diagnosed cancer, other than skin cancers, in North American men. Estimated new cases and disease-related deaths from prostate cancer in the United States in 2016 is 180,890 and 26,120 respectively. Prostate cancer is the second leading cause of cancer death in American men, exceeded only by lung cancer. Men in the United States have about 1 chance in 6 of eventually being diagnosed with this malignancy and about 1 man in 36 will eventually die of the disease (ACS, 2016; NCI, 2016).
The gold standard for diagnosis of prostate cancer is a prostate biopsy. According to the NCI (2016):
Contemporary prostate biopsy relies on spring-loaded biopsy devices that are either digitally guided or guided via ultrasound. TRUS guidance is the most frequently used method of directing prostate needle biopsy because there is some suggestion that the yield of biopsy is improved with such guidance. With the virtually simultaneous clinical acceptance of TRUS, spring-loaded biopsy devices, and the proliferation of PSA screening in the late 1980s, the number of prostate cores obtained from patients with either an abnormal DRE or PSA was most commonly six, using a sextant method of sampling the prostate. There is evidence that the predictable increase in cancer detection rates that would be expected by increasing the number of biopsy cores beyond six does occur; e.g., biopsies with 12 or 15 cores would increase the proportion of biopsied men having cancer detected by 30% to 35%. The extent to which such increased detection will reduce morbidity and mortality from the disease or increase the fraction of men treated unnecessarily is unknown.
The prostate saturation biopsy procedure is based on the assumption that the cancer is small or located in one of the deeper reaches of the prostate gland. The whole gland is sampled without following any particular zonal pattern. It is theorized that the larger the number of evenly distributed samples increases the probability of detecting an underlying cancer, regardless of the tumor size or location. Saturation sampling typically involves 20- to 40-core biopsies, with additional cores taken for larger prostates. Saturation biopsy technique is similar to the sextant or the extended biopsy performed during the TRUS-guided biopsy procedures. A template or grid identifies the exact location of each biopsy core so the exact location and size of the tumor can be mapped. Either regional or general anesthesia or intravenous sedation is typically used. Another method of performing saturation biopsy involves utilizing a transperineal template or grid-based method, known as transperineal template-guided saturation biopsy, or TPSB, using a brachytherapy template. This method has been proposed to be more systematic and allows for improved sampling of the area immediately anterior to the urethra (Raja, 2006).
Proposed indications for TPSB include mapping to determine the location and extent of prostate cancer as a guide to focal treatment (such as ablation); as part of active surveillance of low-risk localized prostate cancer with the aim of reducing the number of biopsies; and as a reference test for evaluation of new methods of imaging the prostate. This procedure is carried out with the individual under local or general anesthesia, requires intravenous prophylactic antibiotics, and involves the placement of a temporary urinary catheter (NICE, 2010). The grid template placed on the perineum during the TPSB procedure contains multiple holes at approximately 5 millimeter (mm) increments. In order to render a 3-dimensional (3D) reconstruction, biopsies are obtained using a standard 18 gauge biopsy gun to include a cross-section of the prostate from the apex to the base at the 5 mm intervals. A larger number of samples are obtained from different parts of the prostate in this procedure referred to as 3D mapping biopsy. This biopsy technique is proposed to improve detection of small cancers compared to other biopsy methods and thereby assist in decision making for primary management of early stage prostate cancer.
Adverse events and complications have been associated with repeat prostate sampling biopsies, including fever, pain, hematospermia/hematuria, positive urine cultures, and rarely sepsis. Sepsis occurs in approximately 0.4% of cases (NCI, 2016). Klein and colleagues (2010) evaluated the effect of multiple core prostate biopsy and periprostatic nerve block on voiding and erectile function. A total of 198 individuals in whom prostate cancer was suspected, were randomly assigned to undergo 10-core prostate biopsy with (71) or without (74) periprostatic nerve block. The 53 men with a history of negative prostate biopsy underwent 20-core saturation prostate biopsy with periprostatic nerve block. The International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) were completed before, and 1, 4 and 12 weeks after biopsy to measure changes in voiding and erectile function, and quality of life. The IPSS was significantly increased in all men at week 1, which persisted at weeks 4 and 12 after saturation biopsy (p=0.007 and 0.035, respectively). Quality of life was significantly affected at all times after saturation prostate biopsy (p=0.001, 0.003 and 0.010, respectively). IIEF scores decreased significantly in all groups at week 1 (p<0.05). The authors concluded that: 1) prostate biopsy causes impaired voiding; 2) saturation prostate biopsy and periprostatic nerve block appear to have a lasting impact on voiding function; and 3) erectile function is transiently affected by prostate biopsy regardless of periprostatic nerve block and the number of cores.
Active surveillance: Treatment approach, also referred to as expectant management or watchful waiting, where tests such as PSA and a DRE are assessed and prostate biopsies are performed on a regular basis.
Biopsy: The removal of a sample of tissue for examination under a microscope for diagnostic purposes.
Digital rectal examination (DRE): An examination of the lower rectum where the medical practitioner uses a gloved, lubricated finger to check for abnormalities of the prostate.
Gleason Grading System: A prostate cancer grading system based on a number range from one to five; the lower the number, the lower the grade, and the slower the cancer growth.
Gleason score: Represents the sum of the two most common Gleason grades observed by the pathologist on a specimen, the first number is the most frequent grade seen.
Prostate: A walnut-shaped gland in men that extends around the urethra at the neck of the urinary bladder and supplies fluid that goes into semen.
Prostate mapping: A procedure involving a combination of multi-sequence magnetic resonance imaging (MRI) techniques and a template guided biopsy system used to diagnosis prostate cancer.
Prostate-specific antigen (PSA): A blood test that measures the amount of a specific prostate-related protein in blood, used to screen for prostate cancer and other conditions. A high PSA level in the blood has been linked to an increased chance of having prostate cancer.
Radical prostatectomy: Surgical procedure for the removal of the prostate.
Transrectal ultrasound (TRUS): An ultrasound test in which the sound waves are produced by a probe inserted into the rectum. In men, the structures most commonly examined with this test are the prostate, bladder, seminal vesicles and ejaculatory ducts.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services are Investigational and Not Medically Necessary:
|55706||Biopsies, prostate, needle, transperineal, stereotactic template guided saturation sampling, including imaging guidance|
|55899||Unlisted procedure, male genital system [when specified as transrectal ultrasound-guided saturation biopsy of the prostate]|
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
3D Mapping Biopsy
Transperineal Stereotactic Template-guided Saturation Prostate Biopsy
Transperineal Template-guided Saturation Biopsy (TTSB)
Transrectal Ultrasound-guided (TRUS) Prostate Biopsy
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Reviewed||05/05/2016||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Reviewed||05/04/2016||Hematology/Oncology Subcommittee review. Updated Description, Rationale, Background, References, and Websites for Additional Information sections. Removed ICD-9 codes from Coding section.|
|Reviewed||05/06/2015||Hematology/Oncology Subcommittee review. Updated Description, Rationale, References, and Websites for Additional Information sections.|
|Reviewed||02/05/2015||MPTAC review. Format changes throughout the document. Updated Rationale, Background, References, and Websites for Additional Information sections.|
|01/01/2015||Updated Coding section with 01/01/2015 HCPCS changes; removed G0417, G0418, G0419 deleted 12/31/2014 and G0416 (no longer applicable).|
|Revised||02/13/2014||MPTAC review. Revised investigational and not medically necessary statement, removing number of core samples. Updated Rationale, Background, Coding, References, and Websites for Additional Information sections.|
|01/01/2014||Updated Coding section with 01/01/2014 HCPCS descriptor changes.|
|Reviewed||02/14/2013||MPTAC review. Updated Rationale, Background, References, Websites for Additional Information, and Index.|
|Revised||02/16/2012||MPTAC review. Revised investigational and not medically necessary statement, separately addressing transrectal and transperineal saturation biopsy techniques. Reformatted and updated the Rationale, Coding, References, and Websites for Additional Information.|
|Reviewed||11/16/2011||Hematology/Oncology Subcommittee review. Updated Rationale, Background, References, and Websites for Additional Information.|
|Reviewed||11/17/2010||Hematology/Oncology Subcommittee review. Updated Description, Rationale, Background, Definitions, References, Websites for Additional Information and Index.|
|Reviewed||11/18/2009||Hematology/Oncology Subcommittee review. Updated Rationale, Background, and References.|
|New||11/19/2008||Hematology/Oncology Subcommittee review. Initial document development.|