Review – Prostate Cancer

Repeat Prostate Biopsy: Rationale, Indications, and Strategies

By: Umberto Capitanioa b , David Pfisterc and Mark Embertond

EU Focus, Volume 1 Issue 2, September 2015, Pages 127-136

Published online: 01 September 2015

Keywords: Prostate cancer, Biopsy, Repeat biopsy, Rebiopsy, Active surveillance, Complications

Abstract Full Text Full Text PDF (437 KB) Patient Summary



The inaccuracy of prostate biopsy in detecting and characterising prostate cancer (PCa) has led to a widespread use of repeat biopsy (RB).


To summarise the most recent data regarding indication, techniques, and clinical implications of RB.

Evidence acquisition

A search of Medline, PubMed, and Scopus identified articles published in the last 7 yr (2008–2014) addressing the role of RB in the PCa setting. Abstracts deemed relevant to the defined review question were screened, and the data were extracted, analysed, and summarised.

Evidence synthesis

RB can be considered either in patients with persistent PCa suspicion after a first negative systematic biopsy or during active surveillance (AS), either to confirm patient enrolment or to monitor the natural progression of the disease. Indication and biopsy techniques differ according to each PCa scenario. Magnetic resonance imaging (MRI)-guided RB has been gaining popularity because of its accuracy in detecting and characterising PCa. Indications for multiple RBs (eg, AS setting) should be carefully evaluated because of the cumulative risk of complications, especially infection. In the next few years, clinical and genetic markers are expected to further improve the ability to determine the need for RB.


RB indications and techniques in persistent PCa suspicion and AS should take into account the evolving field of imaging, management options, and the risk of possible complications. In an RB setting, the introduction in daily clinical practice of MRI-guided targeted biopsy has improved the accuracy in detecting PCa without significantly increasing the risk of finding indolent, low-risk PCa. Referral to specialised care centres should be considered in patients with persistent PCa suspicion to provide the most rationalised management in terms of indication, biopsy technique, complications, pathologic assessment, and, finally, clinical implications of the findings.

Patient summary

A man may require a second prostatic biopsy for a number of reasons. In the current report, we describe why, when, and how a patient should undergo rebiopsy of the prostate.

Take Home Message

Until future findings and more accurate biomarkers are available, repeated biopsy indication and techniques should be considered carefully to maximise the clinical utility of the procedure.

Keywords: Prostate cancer, Biopsy, Repeat biopsy, Rebiopsy, Active surveillance, Complications.

1. Introduction

Repeat biopsy (RB) is usually contemplated in a prostate cancer (PCa) setting in two different clinical scenarios: (1) patients with persistent PCa suspicion after a first negative systematic biopsy and (2) during active surveillance (AS), either to confirm patient enrolment or to monitor the natural progression the disease during the follow-up period. Although some of the characteristics and technical aspects may be similar in these two circumstances, the rationale behind the choice of performing an RB and the clinical implications of the results differ substantially between the two settings.

The motivation behind performing an RB in men with a persistent suspicion of PCa after a negative biopsy is mainly related to the diagnostic uncertainty of the standard transrectal ultrasound (TRUS)-guided biopsy in detecting and characterising the cancer. The standard biopsy strategy is, indeed, subject to sampling error (25–35% and 10–20% for all and significant cancers, respectively) [1], [2], [3], and [4] and provides poor localisation of the disease. More specifically, the primary limitations of initial biopsy include the failure to accurately detect high-grade cancer, imprecise tumour risk stratification, and the detection of small, low-risk, indolent cancers [1], [2], [3], and [4].

In potential candidates for AS protocols, RB has been proposed to confirm patients’ eligibility or, during the follow-up, to eventually switch the patient to a definitive treatment in case of reclassification. In this scenario, RB is used to better classify tumour characteristics or for the early detection of tumour progression [1], [2], [3], and [4].

In the current review, we aim to summarise the most recent data regarding indication, techniques, and clinical implications of an RB in these circumstances.

2. Evidence acquisition

An initial search was carried out using the Medline, PubMed, and Scopus databases. Because of dramatic stage migrations over the last decades resulting from the introduction of prostate-specific antigen (PSA) screening, AS and, MRI, we mainly focussed on publications in the years 2008–2014 to provide data that may be applicable to contemporary PCa patients. However, we did not exclude commonly referenced and highly regarded older publications. The search terms used were (repeat biopsy OR saturation OR rebiopsy) AND (prostate OR prostate cancer) AND (diagnosis OR active surveillance OR radiotherapy OR focal therapy OR PSA failure OR PSA relapse). Abstracts were reviewed for relevance to the defined review question. If it was not clear from the abstract whether the paper might contain relevant data, the full paper was assessed. The references cited in all full-text articles were also assessed for additional relevant articles. Non-English articles were excluded from analysis. Relevant studies were then screened by the three authors, and data were extracted, analysed, and summarised. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart was used to report the number of papers identified and included or excluded at each stage (Fig. 1).


Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analysis flow diagram showing the outcome of the initial and additional searches resulting in the full studies included in the review.

3. Evidence synthesis

3.1. Repeat biopsy after a negative first biopsy

3.1.1. Indication for repeating a prostate biopsy

The most frequent motivation behind an RB is to correct or mitigate previous undersampling or any error associated with previous biopsies. According to international guidelines (Table 1), several aspects should be considered to evaluate the risk of PCa after a first negative systematic biopsy [1], [2], [3], and [4]. A rising and/or persistently elevated PSA level remains the most common indication to perform an RB. The presence, at first biopsy, of an atypical small acinar proliferation (ASAP) or multifocal prostatic intra-epithelial neoplasia (HGPIN) is widely considered an indication for RB at 6–12 mo after initial sampling [5]. In a PSA screening scenario, the risk of having PCa 4 yr after an initially negative screen is <4%. In this case, the indication for RB should be evaluated according to patient age, PSA level, digital rectal examination (DRE), family history, and prostate volume [6]. Finally, in the most recent guidelines, the use of additional biomarkers has been suggested to improve specificity in the RB setting (Table 1). Specifically, free-to-total PSA ratio (%fPSA), PSA density, and PSA velocity have been proposed to be helpful markers in the decision of when to perform an RB [1], [2], [3], and [4]. Related to this, studies have shown that the prostate cancer antigen 3 (PCA3) score and Prostate Health Index (PHI) may improve the accuracy of PSA value and %fPSA in predicting the presence of PCa at RB [7], [8], [9], and [10]. Moreover, several statistical tools have been developed to predict the risk of PCa after an initial negative biopsy. Moussa et al included several variables (age, PSA value, PSA kinetics, family history, ASAP, HGPIN, DRE, months from previous negative biopsy session, and number of previous negative cores) in a nomogram, which yielded an accuracy of 72% in predicting PCa at RB [11]. Similarly, Rochester et al developed a model including age, PSA value, PSA velocity, %fPSA, prostate volume, and DRE. This risk model had an accuracy of 82% in predicting the outcome, allowing for a 39% reduction in the need for RB, although the model underperformed in the validation model (area under the curve: 70%) [12]. Finally, a nomogram including %fPSA, previous HGPIN, DRE, PSA value, and PSA kinetics achieved an overall accuracy of 86% in predicting the presence of PCa at RB [13].

Table 1 International guidelines depicting the role and the characteristics of repeated biopsy in different clinical scenarios

TopicEuropean Association of Urology [1] and [62]American Urological Association [34]National Comprehensive Cancer Network [3]National Institute for Health and Care Excellence guidelines [4]
RB after a negative first biopsyIndications are:
• Rising and/or persistently elevated PSA levels
• Suspicious DRE, 5-30% risk of cancer;
• ASAP, 40% risk of cancer;
• Extensive (multiple biopsy sites) prostatic intra-epithelial neoplasia, 20-30% risk of cancer.
Saturation biopsy, taking tissue from >20 locations, may be considered in men with persistently elevated PSA levels and multiple previous negative prostate biopsy specimens.For men with multiple previous negative biopsy specimens, a saturation biopsy may be considered. Stratification of risk and use of biomarkers that improve specificity such as PCA3 or %fPSA.
Multiparametric MR plays an increasing role in the evaluation for RB.
Consider multiparametric MRI (using T2-imaging and DWI) for men with a negative TRUS 10–12 core biopsy to determine whether another biopsy is needed.
Do not offer another biopsy if the multiparametric MRI (using T2-imaging and DWI) is negative, unless any of the risk factors listed are present:
• Abnormal DRE findings.
RB in active surveillance protocolsAS is based on repeated DRE, PSA testing, and, most importantly, RBs. Early repeated confirmatory biopsies have become an important part of the selection process and are based on the risk of underdetection of grade 4 at the initial biopsyAn ideal regimen for AS has not been defined but could include periodic physical examination and PSA testing or periodic RB to assess for sampling error of the initial biopsy as well as for subsequent progression of tumour grade and/or volume.Needle biopsy of the prostate should be repeated within 6 mo of diagnosis if initial biopsy obtained <10 cores or was assessment discordant.
An RB should be considered if prostate exam changes or PSA level increases, but neither parameter is very reliable for detecting PCa progression.
An RB should be considered as often as annually to assess for disease progression, because PSA kinetics may not be as reliable as monitoring parameters to determine progression of disease.
RBs are not indicated when life expectancy is <10 yr or appropriate when men are on observation.
At 1 yr after AS enrolment. If there is concern regarding clinical or PSA changes at any time during AS, reassess with multiparametric MRI and/or RB.

%fPSA = free-to-total PSA ratio; AS = active surveillance; ASAP = atypical small acinar proliferation; DRE = digital rectal examination; DWI = diffusion-weighted imaging; HGPIN = high-grade prostatic intra-epithelial neoplasia; MR = magnetic resonance; MRI = magnetic resonance imaging; PCA3 = prostate cancer antigen 3; PSA = prostatic-specific antigen; RB = repeated biopsy; RT = radiotherapy; TRUS = transrectal ultrasound.

Last, it has been suggested that the addition of genetic markers to current clinical parameters may improve PCa risk prediction as well [14]. For instance, hypermethylation of genes such as glutathione-S-transferase P1 (GSTP1) and adenomatous polyposis coli (APC) has been suggested as a potential indicator of the need to perform an RB [15]. The improvement obtained with all these clinical and genetic markers is actually modest but may be beneficial for better determining the need for RB [14] and [15].

In this context, one controversial topic is related to the number of procedures (number of biopsy sessions) that patients should undergo to exclude PCa presence. Often, multiple biopsy sessions are a direct consequence of the inadequacy of the performed biopsy [16]. Although PCa detection is inversely related to the number of biopsy sessions performed [16], PCa can be found at each round of sampling [17]. However, as reported, for instance, by Stav et al, virtually all tumours detected after a series of three negative biopsies are of low volume and indicated well-differentiated disease, even in patients with a persistently high suspicion of cancer (PSA value >10 ng/ml; PSA velocity >0.75 ng/ml per year, and %fPSA <0.2) [18]. Since biopsy repetition increases the risk of overdiagnosis due to the detection of low-grade PCa [19] and [20], early consideration of MRI-guided, targeted RB and the referral to specialised care centres is warranted.

3.1.2. Transrectal ultrasound-guided versus transperineal template versus magnetic resonance imaging-guided biopsy

The false-negative rate of transrectal systematic biopsy may be as high as 47% [21] (Table 2). Traditionally, transrectal systematic biopsy has been the most widely used technique due to its user friendliness. Transperineal template biopsy has the benefit of potentially detecting additional PCa, especially in the anterior zone of the prostate [21] and [22], but it may require general anaesthesia with a potential increased risk of morbidity. MRI-guided biopsy has been gaining popularity due to its accuracy in detecting and characterising intermediate and high-grade PCa [23]. In a recent meta-analysis, Nelson et al compared the cancer detection rate between TRUS versus transperineal versus MRI-guided biopsy. Their study included 46 studies with a total of 4657 patients [24]. Cancer detection rates were estimated to be 28% (95% CI, 22–34%), 37% (95% CI, 31–42%), and 37% (95% CI, 30–43%) for transrectal, transperineal, and MRI-guided biopsy, respectively. After taking into account the study variances, the cancer detection rates were calculated to be 30%, 37%, and 38% for transrectal, transperineal, and MRI-guided biopsy, respectively (p = 0.06 [transperineal vs transrectal biopsy] and p = 0.03 [MRI-guided vs transrectal biopsy] [24]. Notably, MRI-guided biopsy required the fewest biopsy cores to achieve the greatest cancer detection rate [24].

Table 2 Recent reports assessing the role of repeated biopsy after first negative sampling and within active surveillance protocols*

AuthorsYearPatients included, no.Cores taken, no.Saturation samplingTargeted samplingApproach, GuidanceCDR, %AS
Reclassification, %
Active treatment delivered, %
After negative first biopsy
Abdollah et al [63]201114024YesNoTR, TRUS31
Scattoni et al [28]201134024YesNoTR, TRUS28
Zaytoun et al [32]2011663
20.7, 20 (20–24)
12.3, 12 (12–14)
Taira et al [21]201029425.7YesNoTR, TRUS47
Shimbo et al [64]20097714NoNoTR, TRUS35
Rochester et al [12]2009110>10, NA (NA)NoNoTR, TRUS31
Stav et al [18]20082762, NA (41–76)YesNoTR, TRUS11
Yuasa et al [65]20081278, NA (NA)NoNoTR, TRUS18
Leite et al [66]20087612, NA (NA)NoNoTR, TRUS8
Benecchi et al [13]200841912, NA (12–24)NoNoTR, TRUS31
Tan et al [67]2008142NA, 20 (NA)MixedNoTR, TRUS23
Haese et al [68]200846312, 16 (10–NA)NoNoTR, TRUS28
Simon et al [69]20084064, NA (39–139)YesNoTR, TRUS45
Ekwueme et al [22]201327028, NA (16–43)YesNoTP, TRUS55
Abdollah et al [63]201114024YesNoTP, TRUS26
Dimmen et al [70]20116919.9YesNoTP, TRUS55
Pal et al [71]20114036YesNoTP, TRUS40
Novara et al [72]201014324YesNoTP, TRUS26
Sonn et al [25]201410515, NA (NA)NoYesTR, MRI34
Roethke et al [73]20121004NoYesTR, MRI52
Hadaschik et al [74]20114923.7YesNoTR, MRI45
Franiel et al [75]2011544NoYesTR, MRI39
Hambrock et al [76]2010684NoYesTR, MRI59
Sciarra et al [77]201090NANoYesTR, MRI49
Testa et al [78]201054NANoYesTR, MRI41
AS: confirmatory biopsy
Hu et al [42]2014113NA, 13 (NA)NoYesTR, MRI7637NA
King et al [38]20135212, 12 (12–12)NoNoTR, TRUS441717
Motamedinia et al [39]20126017, NA (6–32)NoNoTR, TRUS553217
Barzell et al [40]20121249.5, 10 (NA)
90, 89.7 (NA)
Abouassaly et al [48]20085220, NA (NA)YesNoTR, TRUSNA38NA
Berglund et al [37]2008104NA, 14 (NA)NoNoTR, TRUS742720
AS: follow-up
Welty et al [36]2014685NA, 13 (11–16)NoNoTR, TRUSNA43
Barayan et al [51]2014300NA, NA (6–16)NoNoTR, TRUS3220
Bul et al [52]2012757NA, NA (8–12)NoNoTR, TRUS22NA
Porten et al [49]2011377NANoNoTR, TRUS3420
Kotb et al [79]2011102NANoNoTR, TRUS10-31NA
Whitson et al [53]2011241NANoNoTR, TRUS23NA
San Francisco et al [80]201112020, 20 (20–20)NoNoTR, TRUS30NA
Tseng et al [81]201045NA, NA (12–14)NoNoTR, TRUSNANA
Adamy et al [82]2011238NANoNoTR, TRUS26NA
Ross et al [83]2010290NANoNoTR, TRUS3535
Al Otaibi et al [50]20081867, 8 (6–16)NoNoTR, TRUS3631

* Data are further stratified according to the clinical scenario.

Where three values given, data are given as mean, median (range).

After three previous negative biopsies.

CDR = cancer detection rate; MRI = magnetic resonance imaging; NA = not available; RB = repeat biopsy; TP = transperineal; TR = transrectal; TRUS = transrectal ultrasound.

As anticipated in the above-cited meta-analysis [24] and recently confirmed by the most updated National Comprehensive Cancer Network guidelines, MRI will play an increasing role in evaluating the need to perform an RB [3]. Sonn et al found a cancer detection rate (CDR) of 34% using MRI-guided fusion technology for RB, with 72% of detected PCas being clinically significant (Gleason 3 + 4 or Gleason 6 with maximal cancer core length >4 mm) [25]. Moreover, MRI-guided RB identified significantly more clinically significant cancers relative to standard sextant biopsy (91% vs 54%).

In a series of 438 consecutive patients with an increased PSA level and at least one prior negative biopsy who underwent MRI, Hoeks et al reported a CDR of 41% using in-bore targeted biopsy, with 87% of these cancers found to be clinically significant (Gleason grade 4–5 or PSA level >10 ng/ml or PSA density >0.15 ng/ml per millilitre; Gleason grade 4-5 or stage pT3 or tumour volume >0.5 ml in case of prostatectomy) [84]. In a similar cohort of 100 patients, Pepe et al reported a CDR of 40.7% with accuracy, sensitivity, specificity, and positive and negative predictive value of MRI in diagnosing Gleason 7–10 PCa of 81%, 100%, 79%, 56%, and 100%, respectively [26]. Borkowetz et al reported a study cohort of 195 RB patients who underwent MRI-guided transperineal RB (with a mean of nine cores) and additionally underwent a systematic transrectal biopsy (mean of 12 cores) [27]. The overall detection rate was 44% (85 of 195 patients) in targeted biopsy and 32% (62 of 195) in systematic biopsy (p = 0.002). Regarding Gleason score upgrading, 44% more Gleason 7–10 PCa were detected using additional targeted biopsy compared to systematic biopsy alone. Conversely, 12% more Gleason 7–10 cancers were found using systematic biopsy in addition to targeted biopsy, confirming the need to perform a traditional systematic biopsy in addition to the MRI-guided procedure [27].

3.1.3. Number and location of cores

Beyond the difficulties in identifying RB candidates, the second most challenging aspect is deciding the number and the location of the cores to be taken to maximise the accuracy of a second prostate sampling. Efforts to overcome sampling error include performing multiple RBs and increasing the core number, and have resulted in the overdetection of indolent cancers, morbidity attributed to unnecessary biopsies, and an increase in costs [1], [2], [3], and [4]. Furthermore, increasing the number of cores beyond the extended systematic TRUS-guided biopsy usually results in a marginal increase in the overall detection rate and simply increases the rate of indolent cancer detection [28]. The majority of the currently available guidelines suggest performing saturation biopsy for men with multiple, previous negative biopsies [1], [2], [3], and [4]. Anterior and transitional zone sampling should be considered at RB, since it has been shown that up to 83% and 35% of patients who undergo a saturation RB harbour PCa in the anterior and transitional area, respectively [22], [29], and [30]. Based on the findings that even initial extended biopsies (>12 cores) miss almost one-third of cancers or result in grade misclassification [31], a saturation approach has been suggested to improve PCa detection. For instance, Zaytoun et al compared the performance of saturation biopsy (n = 663; 20–24 cores) and extended biopsy (n = 393, 12–14 cores) after an initial negative biopsy [32]. PCa was detected in 315 of the 1056 patients (29.8%), but saturation biopsy detected almost one-third more cancers (32.7% vs 24.9%; p = 0.007) with a slightly higher rate of insignificant cancers (40.1% vs 32.6%; Gleason sum 6 or three or fewer positive cores and a maximum of ≤50% of cancer in any positive core; p = 0.2) [32].

Increasing the number of cores is not sufficient to detect the cancer missed at first biopsy: The relationship between the number of biopsy cores taken and the resulting cancer detection rate is not linearly correlated [33]. In fact, the curve tends to plateau, and the increase of cores taken in the template is not equivalent to the increase of detected cancer (Table 2). Interest has increased in defining more efficient biopsy schemes for PCa detection with the minimum number of cores. In a prospective evaluation of 340 consecutive patients who underwent a standardised 24-core RB after a first negative systematic biopsy, Scattoni et al attempted to identify the optimal combination of sampling sites (number and location) to detect PCa [28]. They also showed that the ideal RB scheme varies according to the clinical characteristics of the patient. For instance, for patients with a previous ASAP diagnosis, the most advantageous scheme was a combination of a 14-core biopsy (without transitional area biopsies). For patients with no previous ASAP diagnosis and %fPSA ≤10%, the most advantageous scheme was a 14-core biopsy (including transitional area). Finally, the most advantageous sampling scheme for patients with no previous ASAP and %fPSA >10% was a saturation combination of a 20-core biopsy [28]. These data confirm that cancer detection is influenced not only by the number of cores sampled but also by the exact location of the cores [1], [2], [3], and [34]. Regarding MRI-guided targeted RB, two to four cores are usually taken from the suspicious area in addition to the systematic sextant biopsies. However, to date, the most informative number of cores that should be considered is still not well defined. In this context, MRI may have the potential role to select at RB those men who could advantageously undergo a targeted sampling only (eg, in the anterior area). For instance, Komai et al prospectively performed in 324 men a prebiopsy MRI followed by a combination of transrectal cores (n = 12) plus transperineal cores (n = 14). Significant cancers (defined as biopsy Gleason score ≥4 + 3 or ≥20% positive core or cancer length ≥5 mm) detected by the transperineal 14-core biopsy but not by the transrectal 12-core biopsy were frequent (≤92%) when MRI showed an anterior lesion sporadically (one case) among patients with a negative prebiopsy MRI [35].

In conclusion, the exact number and location of cores in an RB setting should be individualised according to patient and prostate characteristics. Saturation biopsy should be limited to selected cases, as it significantly increases the risk of overdiagnosis without substantial benefit for the patient. Although more, well-performed prospective studies are needed to validate the findings, the literature suggests that prebiopsy MRI and MRI-guided targeted biopsies may help determine which men and which specific prostate areas (eg, targeted only or anterior/transitional zones), respectively, should be undergo RB [35].

3.2. Repeat biopsy in active surveillance protocols

3.2.1. Confirmatory biopsy for enrolment

Roughly 30% of men diagnosed with PCa are considered to have low-risk disease and are potential candidates for AS protocols. However, 18–27% of those men with apparently low-risk cancer will be reclassified at RB into a higher risk category [36] and [37]. Several institutions have reported risk factors for reclassification during AS, including initial biopsy characteristics, PSA velocity, PSA density, RB results, and other variables [36].

Confirmatory biopsy timing differs among centres. The first RB is usually recommended within 12 mo of the diagnostic biopsy, but, in many institutions, the confirmatory RB is performed immediately to confirm patient eligibility for AS. King et al reported on TRUS-guided, 12-core biopsy at an average time of 2.7 mo following diagnosis [38]. Notably, 56% of patients demonstrated no evidence of PCa on RB. Overall, 14 of 23 men with a positive RB showed either an increase in cancer volume or an upgrade of Gleason score. Reclassification to intermediate or high risk was observed in 17% of the AS candidates [38]. In a similar report, Motamedinia et al described a 31.7% reclassification at RB in 60 patients who were candidates for AS at initial biopsy [39]. In the majority of these reports, the absence of cancer at immediate RB predicted a good prognosis with a lower risk of progression during AS [39].

Barzell et al compared the performance of the type of approach used (TRUS vs template transperineal biopsy) in 124 AS candidates who underwent a combined TRUS biopsy plus a template transperineal prostate mapping as a confirmatory strategy [40]. Depending on the definition used, 8–22% versus 41–85% of men had PCa that was reclassified as intermediate or high risk at TRUS versus transperineal RB, respectively. Finally, the sensitivity of repeat TRUS biopsy to identify intermediate- to high-risk disease varied from 9% to 24% with the negative predictive value ranging from 23% to 60% [40].

Among men with cancer who are contemplating AS, MRI-targeted biopsy potentially improves risk stratification and reduces the need for RB [41]. In a study of 388 consecutive patients with low-risk disease who underwent MRI-guided biopsy, Vargas et al reported that 20% were reclassified at confirmatory biopsy [85]. Similarly, Hu et al [42] and Margel et al [43] found that by using MRI-guided biopsy, 36% and 32%, respectively, of the patients who were reclassified at confirmatory biopsy were no longer be suitable for AS (Table 2).

3.2.2. During follow-up

Various AS protocols using different numbers and locations of cores have been proposed. However, widely used surveillance schemes usually include at least a 12-core sampling from each sextant [1], [2], [3], and [4]. Recent findings suggested that saturation and transperineal biopsies increase the progression to treatment in AS follow-up as a possible consequence of more adequate prostate sampling during AS follow-up [44] and [45], especially in the anterior area of the prostate. Specifically, it has been shown in men who underwent a transperineal template-guided mapping RB after two or more previous biopsies, that the cancer detection rate remained high, especially in the anterior-most aspects of the gland [46] and that the majority of AS patients treated with radical prostatectomy for disease progression showed significant (>1 cm) anterior zone PCa [47]. This enhanced sampling may be associated with a beneficial early detection of significant disease but with an increased risk of overtreatment [44]. For instance, Abouassaly et al reported the use of saturation RB at a median of 9 mo after AS enrolment [48]. The disease of 38% of the patients was upstaged (defined as Gleason upgrading or increased disease volume), leading to a recommendation for active treatment. Patients with disease upstaging had significantly fewer cores taken at the initial diagnostic biopsy (11% with ≥20 cores vs 55% with <20 cores; p = 0.002), again highlighting the importance of initial biopsy adequacy [48]. Other reports in the setting of RB during AS follow-up suggested that MRI might result in only a marginal increase in accuracy compared to systematic RB, because of the frequent presence of small, well-differentiated tumours [45].

Porten et al recently described a population of 377 AS patients in which 34% of men were found to have an increase in Gleason grade during follow-up [49]. The majority of men who experienced an upgrade (81%) did so at the first RB, suggesting that men with low-grade, low-stage disease managed with AS who experience early upgrading are more likely to have experienced initial sampling error, whereas later upgrading may reflect tumour differentiation [49]. Comparably, Al Otaibi and colleagues suggested that the result of the first RB appears to have a stronger impact on disease progression (5-yr progression-free survival was 82% vs 50% in positive vs negative first RB; p = 0.02) and should be considered for treatment delivery [50]. Finally, in a recent cohort of 300 PCa patients included in an AS protocol, the risk of progression decreased from 20.9% to 8% and 0% on the second, third, and fourth RB, respectively [51], suggesting that patients who are likely to progress are usually detected in the first 2 yr following diagnosis. Moreover, the clinical features at baseline and during follow-up of an AS cohort have been demonstrated to be associated with short-term reclassification to higher risk at RB. For instance, Bul et al reported data taken from 757 patients included in the Prostate Cancer Research International Active Surveillance (PRIAS) protocol, of whom 163 (21.5%) were reclassified as not suitable for AS during the follow-up period [52]. Analyses showed that reclassification to higher risk was significantly influenced by the number of initial positive cores (two vs one; odd ratio [OR]: 1.8; p = 0.002), higher PSA density (OR: 2.1; p = 0.003), and PSA DT <3 yr (OR: 1.7; p = 0.01). The outcome was not influenced by age, clinical stage, number of cores taken, or PSA levels [52]. Similarly, Whitson et al confirmed that PSA fluctuations should be neglected during the first 24 mo of surveillance in men with well-staged, low-risk PCa, making RB the most accurate tool to assess previous misclassification and/or tumour progression [53].

3.3. General considerations

3.3.1. Repeat biopsy: Should the antibiotic prophylaxis be different?

A pathophysiology study confirmed that a small but statistically significant increase in chronic inflammation should be expected when patients undergo serial biopsies within an active surveillance protocol [54]. Moreover, previous exposure to antibiotics puts a candidate for RB at a potential higher risk of infectious complications. A range of infectious complications may occur after prostate needle biopsy, including asymptomatic bacteriuria, urinary tract infection, and bacteremia accompanied by sepsis. In addition, studies have reported that 11–22% of men undergoing prostate needle biopsy harbour fluoroquinolone-resistant organisms within the rectum [55]. Ehdaie et al showed that the risk of postbiopsy infection for a man who has undergone one or two previous biopsies is about 2% and then rises to 5%, 10%, and 15% for patients who have undergone three, four, and five or more biopsies, respectively [55]. In light of an increasing prevalence of fluoroquinolone resistance, recent data suggest a tailored approach to prophylaxis [1], [3], and [34]. In particular, it is suggested that screening for fluoroquinolone-resistant pathogens using a rectal swab culture prior to biopsy can direct antibiotic prophylaxis and significantly reduce infectious complications [56].

3.3.2. Rate of complications in the repeat-biopsy setting

Using the Surveillance Epidemiology and End Results (SEER)-Medicare database, Loeb et al identified 3640 men who underwent multiple biopsies and showed similar 30-d hospitalisation rates between RB patients and the randomly selected control population [57]. They demonstrated that although each biopsy was associated with a significant risk of complications, the RB procedure itself was not associated with a greater risk of serious complications requiring hospital admission compared to the initial biopsy setting [57]. Controversial results were observed in the Prostate, Lung Colorectal and Ovary (PLCO) trial, in which noninfection complications were less frequent in patients who underwent RB relative to naive patients (OR: 0.3; 95% CI, 0.1–0.9) [58]. Finally, findings suggest that erectile function is not significantly affected by RB [59] and [60]. Patients should be informed that temporary erectile dysfunction may be present after RB, especially after a saturation procedure [61].

Although the risk of complications in the RB setting is low, it is mandatory to highlight that each subsequent biopsy increases the cumulative rate of complications for an individual patient. Indeed, some reports have suggested that the number of previous prostate biopsies is significantly associated with an increased risk of infectious complications. For instance, Ehdaie et al showed a 1.3-fold higher risk of infection for every previous biopsy (p = 0.04) in a cohort of 403 US patients [55].

4. Conclusions

The inadequacy of standard biopsy in detecting and characterising PCa has led to the increase of RBs in several urologic scenarios. RB indications and techniques in persistent PCa suspicion and AS should take the evolving field of imaging, as well as management options and the possible risk of complications, into careful consideration.

In an RB setting, the introduction to daily clinical practice of MRI-guided targeted biopsy has improved the accuracy in detecting PCa without significantly increasing the risk of finding indolent, low-risk PCa. In this context, given the limitations and the clinical difficulties depicted in the current review, it appears essential to refer patients who may be candidates for RB to specialised centres. A dedicated, multidisciplinary team of urologists, radiologists, and pathologists can provide the most rationalised management in terms of clinical indication, biopsy techniques, complications, pathologic assessment, and, finally, clinical implications of the findings. Additional insights regarding biopsy techniques, new imaging technology, and novel biological markers are desirable.

Author contributions: Umberto Capitanio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Capitanio, Pfister, Emberton.

Acquisition of data: Capitanio, Pfister, Emberton.

Analysis and interpretation of data: Capitanio, Pfister, Emberton.

Drafting of the manuscript: Capitanio, Pfister, Emberton.

Critical revision of the manuscript for important intellectual content: Capitanio, Pfister, Emberton.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Capitanio, Pfister, Emberton.

Other (specify): None.

Financial disclosures: Umberto Capitanio certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.


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a Department of Urology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy

b Division of Experimental Oncology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy

c Department of Urology, RWTH Aachen University, Aachen, Germany

d Division of Surgery and Interventional Science, University College London, London, UK

Corresponding author. Department of Urology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298.

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