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Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study
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Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study Giancarlo Marra , Alessandro Marquis , Stefano Tappero , Daniele D’Agate , Marco Oderda , Giorgio Calleris , Marco Falcone , Riccardo Faletti , Luca Molinaro , Andrea Zitella , Laura Bergamasco , Paolo Gontero PII: DOI: Reference:
S0090-4295(20)30162-X https://doi.org/10.1016/j.urology.2019.11.078 URL 21979
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Urology
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24 July 2019 24 October 2019 12 November 2019
Please cite this article as: Giancarlo Marra , Alessandro Marquis , Stefano Tappero , Daniele D’Agate , Marco Oderda , Giorgio Calleris , Marco Falcone , Riccardo Faletti , Luca Molinaro , Andrea Zitella , Laura Bergamasco , Paolo Gontero , Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study, Urology (2020), doi: https://doi.org/10.1016/j.urology.2019.11.078
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study Authors Giancarlo Marra1, Alessandro Marquis1, Stefano Tappero1, Daniele D’Agate1, Marco Oderda1, Giorgio Calleris1, Marco Falcone1, Riccardo Faletti2, Luca Molinaro3, Andrea Zitella1, Laura Bergamasco2 and Paolo Gontero1 1
Department of Urology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy 2
Department of Radiology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy 3
Department of Pathology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy
Key words 1. Prostate 2. Prostate cancer 3. Prostate biopsy 4. Prostate fusion biopsy 5. Prostate mp-MRI targeted biopsy 6. Multi-parametric MRI of the prostate.
Corresponding author Dr. Alessandro Marquis e-mail: [email protected] Department of Urology San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, C.so Bramante 88/90 10126 Turin Italy Tel: +39 011 6336591 Fax: +39 011 6335707
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Abstract Objective: To evaluate the feasibility of ‘’in-office’’ TPFBx under LA. Materials and Methods: We prospectively screened for eligibility data of 724 consecutive men undergoing either TPFBx (target and systematic cores) or TPSBx (systematic cores only) from September 2016 to June 2018 due to suspicion of PCa, according to pre-defined exclusion criteria. Results: We included 459 men (TPFBx n=279 including n=338 mpMRI lesions, Pi-RADS 4 in 63.6%; TPSBx n=180). Median procedural time and maximum pain were 19 minutes and 5 NRS points; pain was highest at the time of LA. Only one major complication occurred (Clavien 3a). Haematuria and hematospermia were frequent (72.6% and 54.2%). Vaso-vagal reactions and AUR were rare (0.7% and 0.4%). No cases of UTI and one case of fever were recorded. No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx (p=0.86 and p=0.89). In comparison with TPSBx the sole differences were pain during prostatic sampling (p=0.03), duration of haematospermia (p<0.0001) and procedural time (p<0.001) all higher for TPFBx. csPCa was detected in n=150 (53.8%) patients in the TPFBx group (34.9%, 51.7% and 75% of Pirads 3,4 and 5 respectively). Addition of systematic cores detected n=25 csPCa that were missed by targeted cores (17.4% of all csPCa). Conclusions: TPFBx under LA are feasible, yielding high tolerability, low complications, no impact on erectile and urinary function and good csPCa detection. Addition of systematic to targeted cores remains recommended. Further studies are needed to confirm our findings.
Abbreviations PCa=Prostate Cancer mpMRI=multiparametric MRI Bx= biopsies TR=transrectal TP=transperineal TPFBx= transperineal free-hand mpMRI targeted fusion biopsies LA=local anesthesia TPSBx=Systematic transperineal free-hand biopsies csPCa=clinically significant prostate cancer
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1. Introduction After remaining largely unchanged for more than three decades, PCa diagnostic pathway has been revolutionized by mpMRI and mpMRI-targeted biopsies. Level 1 evidence now supports the use of mpMRI before prostate biopsy compared to the standard PSA and digital rectal exam based pathway alone [1-5]. However, several controversies remain, including the methods used to carry out the biopsies, whether in a cognitive, mpMRI in-bore or software-based fashion, the optimal number of targeted cores to be taken and the need of adding systematic cores to the targeted ones [3]. On the contrary, whether a prostate biopsy should be performed through the perineal or through the rectal route dates as far back as the nineties [6]. To date no clear answers in favor of one or the other approach are present and the debate enters unsolved the ‘’mpMRI-targeted biopsy era’’ [3, 7, 8]. On one hand, by avoiding the rectal route, TP Bx do not cause rectal bacteria inoculation in the prostate and may thus reduce infections. This is a major supporting argument for those favoring the TP approach in view of the alarming rise of quinolone-resistant bacteria at pre-biopsy rectal cultures and of post-biopsy sepsis-related complications [9, 10]. Some do also claim the TP route allows higher accessibility to certain areas of the prostate including apex, dorsolateral and anterior prostate segments, possibly resulting in higher PCa detection [3, 11]. On the other hand, those supporting the TR route argue for its higher deliverability in the outpatient setting, including: i) higher tolerability compared to TP, with many TP series reporting the use of general anesthesia; ii) lower comorbidity, especially in terms of urinary retention with some believing it more frequently occurs after TP Bx; iii) lower procedural timings [3].
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To our knowledge, no large prospective studies ever detailed the feasibility of TP mpMRI-targeted biopsies in an in-office setting [3]. Hence, we performed a prospective study to assess the feasibility of TP free-hand mpMRI targeted fusion biopsies under local anesthesia.
2. Methods 2.1 Study Outcomes and Outcome Measures Primary outcome was to assess the feasibility of TPFBx in terms of pain, peri- and post-procedural complications and urinary and erectile function changes. Secondary outcomes were: i) to validate TPFBx feasibility by comparing the results with systematic TP Bx, hypothesizing that adding targeted cores to systematic cores does not significantly impact on pain, peri- and post-procedural complications and urinary and erectile function; ii) csPCa detection rate of TPFBx.
2.2 Study Cohort and Data Collection From September 2016 to June 2018 we prospectively screened for study eligibility n=724 consecutive men undergoing either TPFBx (target cores and systematic cores) or TPSBx (systematic cores only) at San Giovanni Battista Hospital, Turin, Italy (ethical committee approval protocol 39636). Indications to perform Bx were: positive mpMRI (Pi-RADSV2 score≥3) performed due to elevated PSA and/or suspicious DRE - TPFBx; no mpMRI being performed or negative mpMRI with persistent PCa suspicion due to elevated PSA and/or suspicious DRE - TPSBx. Indications to mpMRI prior to Bx or following a previous negative Bx were at referring Urologist’s discretion. We ‘’a priori’’ excluded men with: i)PSA >20ng/mL; ii)age >80; iii)previous PCa diagnosis; iv)colostomy or rectal amputation; v)congenital coagulation alterations and/or who did not interrupt anticoagulant therapy (aspirin use was not discontinued at the time of Bx; patients 4
using anticoagulants or antiplatelet agents other than aspirin discontinued treatment or bridged with heparin depending on the risk deriving from therapy discontinuation); vi)no antibiotic prophylaxis; vii)no consent for study participation; viii)not providing follow up information. Study flowchart is represented in Supplementary Figure 1.
Data collection was performed at four different time frames: i)before the procedure (baseline features); ii)during the procedure (pain, peri-procedural complications and procedural timings); iii)immediately after the procedure, before patient discharge (early onset complications); iv)at 40 days from the biopsy during the first clinical follow-up visit (complications, functional outcomes and final pathological results).
Baseline features included detailed general and urological history and comorbidity status, evaluated using ASA score and Charlson Comorbidity Index. Urinary and erectile functions were assessed using IPSS and IIEF-5 respectively. Peri-procedural pain was determined using a 1 to 10 numeric rating scale -NRS. Complications were graded according to the Clavien-Dindo Score [12] and reported following the EAU Guidelines on reporting urological complications [13]. CsPCa was defined according to the START criteria [14].
3. Biopsy Technique (Figure 1) 2.3.1 Local Anesthesia All procedures were carried out in an in-office setting using the same LA technique. The patient is placed in the dorso-lithotomy position. Perineal skin is disinfected using a clorexidine solution. Under TRUS guidance 20cc (10cc per lobe) of lidocaine 1% are injected at the posterior prostate apex on the capsule surface. After peri-prostatic injection, while exiting the needle (without 5
further puncture), local anesthetic is also injected in perineal muscular planes, subcutaneous perineal planes and underneath the perineal skin, in the areas that will be subsequently traversed for the biopsy (Figure 1A).
2.3.2 Prostate Biopsy Oral ciprofloxacin was administered twice daily for three days starting the day before the procedure. Biopsies were collected using an 18-gauge, 22mm depth standard coaxial Bard needle (Bard, NJ, USA). Ultrasound images and fusion of ultrasound and mpMRI images was performed using the Esaote platform (EsaoteMyLab, NaviSuite5.0; Genova, IT), a rigid fusion platform allowing ‘’live’’ navigation and real-time monitoring of a correct overlap of ultrasound and mpMRI images and targets. The technique is detailed in Figure 1. First, when performing TPFBx, four cores per target are taken (Figure 1B). In case of patients’ movements causing target misalignment the procedure is interrupted to perform Ultrasound and mpMRI images fusion again before continuing the targeting. Subsequently, systematic cores are taken in the posterior and posterolateral prostate including a total of 12-cores (Figure 1C and 1D), with the anterior prostate quadrants and transition zone not being routinely biopsied (targeted biopsy of the anterior quadrants and transition zone is performed in case of suspicious mpMRI and/or suspicious ipo-echoic areas but not in case of negative mpMRI and/or systematic sampling). The technique did not involve the use of an introducer, with the perineal skin being punctured for each biopsy core taken and thus allowing: i) higher flexibility of the needle, especially in large prostates where possible
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interference with the pubic arch may be encountered; ii) less chance to conflict/interfere with the ultrasound probe.
3.1 mpMRI Imaging and Pathology We included both mpMRI performed at our center (n=149) or not (n=118). mpMRI protocol performed at our institution has been previously described [15]. All internal and n=93 external mpMRIs were reviewed by an experienced radiologist dedicated to prostate mpMRI and blind to clinical data using Pi-RADS V2 score and sectors [16]. All biopsy specimens were evaluated by a dedicated senior uro-pathologist.
2.5 Statistical Analysis Two open sources (www.openepi.com and www.vassarstats.net) and StatPlus:macLE v5.9.92 (Analyst Soft, CA, USA) were used. Continuous variables satisfying Kolmogorof-Smirnov/Lillienfor test and Shapiro Wilks W test were expressed as median (IQR) and compared using non-parametric Mann-Whitney test. Categorical variables were expressed as absolute numbers and/or percentages and compared using Chisquare or Fisher’s exact test when appropriate.
4. Results 4.1 Baseline Features Baseline features are shown in Table 1. Overall in the TPFBx group mean age and PSA were 68 years and 6.4 ng/mL respectively; 36.8% had equivocal DRE, 13.6% family history of PCa, 7.6% previous BPH surgery and 34% were taking medical BPH-treatments. Overall 338 lesions were identified in 279 men, the majority of which being Pi-RADS 4 (63.6%). 7
No major baseline differences were noted in factors potentially influencing complications, pain and PCa detection amongst TPFBx and TPSBx except number of previous biopsies and of cores taken, both higher for TPFBx (both p<0.001).
4.2 Peri-procedural outcomes Peri-procedural outcomes are displayed in Table 2 and Figure 2. Mean procedural time of TPFBx was 19.1 minutes, higher than TPSBx (p<0.001). The procedure was well tolerated with maximum experienced mean pain being 4.7 NRS points, with pain being highest at the time of LA and no patients discontinuing the procedure. No differences with TPSBx were noted with the exception of pain during prostatic sampling, slightly higher for TPFBx (p=0.03).
4.3 Complications Only one major complication occurred (Clavien 3a; AUR with permanent indwelling catheter until endoscopic treatment). Most frequent collateral event was haematuria, occurring in 72.6% and lasting a mean of 8.3 days, followed by haematospermia, occurring in 54.2% and lasting a mean of 15.3 days. Eight men experienced post-procedural vaso-vagal reactions. Two patients who were already scheduled for BPH surgery before the procedure had AUR. No cases of UTI and one case of fever, self-resolving without antibiotics administration and being referred by the patient two days after the procedure were recorded. No significant complications differences were noted with TPSBx, with the exception of longer duration of haematospermia (p<0.0001).
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4.4 Impact on erectile and urinary function No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx with mean IPSS and IIEF-5 variations being -1.2 (p=0.86) and -0.9 (p=0.89) respectively. Similarly, no major differences were noted in the TPSBx group (IPSS p=0.9; IIEF-5 p=0.66).
4.5 Detection Rate (Supplementary Table 1) csPCa was detected in n=150 (53.8%) patients in the TPFBx group (34.9%, 51.7% and 75% of Pirads 3,4 and 5 respectively), with Gleason score 7 in the majority of the cases (84%). In the TPSBx group csPCa was detected in n=81 (45%). Addition of systematic cores detected n=25 csPCa that were missed by targeted cores (17.4% of all csPCa).
5. Discussion To our knowledge, this is the largest study to prospectively evaluate TPFBx under LA from a 360degree perspective, including complications, procedural timings, impact on erectile and urinary function and PCa detection. Overall, TP freehand sampling being performed using an mpMRI targeted and/or systematic technique proved feasible and safe in an in-office setting using LA and yielded acceptable PCa detection. The addition of targeted to systematic cores did not significantly impact on overall pain, complications, urinary and erectile function. Several aspects of our work are of relevance. On one hand our results constitute a helpful tool for patient counselling before TP biopsies. On the other hand, the present study places itself amongst the growing body of evidence in support of TPFBx under LA use, strengthening the evidence of very recent reports [3, 7, 17]. 9
First, pain is low showing a high tolerability and no patients interrupted the procedure due to perceived pain. As found by others [7, 17], the highest degree of pain is experienced at the time of LA. Contrarily, sampling is less painful being slightly worse than ultrasound probe rectal insertion. These findings are confirmed by the comparison of TPFBx and TPSBx: as the highest pain scores are recorded during the anesthesia, no major differences in maximum perceived pain were recorded (p=0.2). When assessing sampling alone, the increased number of cores deriving from the addition of targets, and probably the longer procedural timings of TPFBx, resulted in pain increase (p=0.03). However, we do believe the one point NRS difference compared to TPSBx as not being clinically meaningful. Furthermore, this difference did not translate into any dissimilarity in the maximum perceived pain. Second, despite others reported longer procedural timings, the procedure is relatively fast, generally lasting less than 20 minutes [17]. Our institutional experience with TP LA sampling, which also became the standard Bx technique since 2013 may partly explain this difference. Third, complications are low, generally reflecting previous findings of TP and TR series [19, 20]. Bleeding was extremely rare so as for vaso-vagal reactions which did not hamper the accomplishment of the biopsy. Hematuria and hematospermia occurred frequently. Nonetheless, all these events were self-resolving. Urinary retention and infectious complications deserve a separate mention. Despite no RCT ever showed any difference between the transrectal and transperineal routes [21], they are usually considered amongst major drawbacks and advantages of TP biopsies respectively [3]. Concerning retention, its incidence in TP series varies widely, being described in up to 24% of men [19, 20]. However, studies with higher retention rates are usually those performing template mapping approaches where 1 core is taken every 2-3cc of the gland reaching up to 100 cores in large prostates. Also, these procedures are performed under general anesthesia which is another 10
precipitating factor favoring retention. As noted by others [7, 19, 20, 22], in our series retention was rare, occurring in less than 1%. Furthermore, the three retention cases were men already scheduled to undergo BPH surgery. Hence, although it may occur, when using up to 18 TP cores and a LA technique, retention is negligible and comparable to the TR approach [19, 20]. Moreover, no significant alteration in urinary symptoms was noted at 40 days. Although some degree of local edema is well-known to occur following biopsies, it is unlikely to significantly affect micturition, at least from the patient perspective. As for infections, no cases of UTI and uro-sepsis were recorded. Fever, when it occurred, may have been unrelated to the biopsy as it self-resolved with no additional antibiotic needs in maximum 3 days after the procedure together with flu-like symptoms. This is no surprise and confirms the extremely low infectious risk of the TP route [23]. Meyer et al just published the results of the first 43 men undergoing ‘’antibiotic free’’ TP prostate biopsy in the US, describing no infectious cases [8]. In our series we used quinolones as antibiotic prophylaxis. As one in five to almost one in two men harbors quinolones resistant bacteria at pre-biopsy rectal culture [3, 10] our results support decreasing antibiotic needs when using the TP route. Given the alarming increase world-wide of post-procedural fever, hospital re-admission and sepsis following TR biopsies [9, 19] several groups suggested upfront antibiotic augmentation [10, 24]. Recently, two studies even assessed carbapenem-based prophylaxis [25, 26]. In our view diminishing infectious rates in the short term using third-line antibiotics does not seem the correct answer to the global warning on antibiotic abuse and will likely further increase resistance [27]. From an infectious perspective, although no RCT do exist proving TP superiority, we favor this approach over the TR. Fourth, in line with previous studies, we confirmed no impact on erectile function. Despite periprostatic nerve block and edema of neurovascular bundles have been suggested as possible 11
mechanisms altering erections, even in case they occur immediately after the procedure, they do not cause any significant nor permanent variations on a longer term [19, 20]. Fifth, detection of csPCa is promising, being in line with recently published multicenter series and trials [1, 4, 5, 28] and does not seem to be hampered in an in-office LA setting. Interestingly, we did find exceedingly high and low proportions of csPCA and ncsPCa respectively, which were confirmed by the pathological review, mainly related to the low incidence of low volume Gleason Score 6 in our series. It remains unclear whether this derives from the TP approach and it certainly warrants further investigation. Importantly, our study was not designed to estimate potential advantages of mpMRI targeting as the benefits of the mpMRI-based pathway are no more a matter of debate [1, 4, 5]. Furthermore, by including both primary and secondary biopsy settings and external mpMRIs being performed with different protocols, our cancer detection does not refer to a specific patient group. Oncological outcomes were not a primary endpoint and were reported to allow an acknowledgment of technique results. Nonetheless, we found approximately one on five men having csPCa would have been missed by targeted cores, if not performing systematic sampling. Given the overall low morbidity and complications rate, our findings support the addition of systematic to targeted cores when performing TPFBx under LA [4, 5, 28]. The single center nature of the present work requires others to reproduce our findings. We are currently performing a multicenter study in collaboration with other centers and results update has been planned in the near future to confirm the feasibility of TPFBx in an in-office setting and to expand their use.
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6. Conclusions Transperineal mpMRI-targeted biopsies under LA are feasible, yielding high tolerability, low complications with negligible urinary retention and infectious risks, no impact on erectile and urinary function and good csPCa detection in an ‘’in-office’’ setting. The addition of systematic to targeted cores remains recommended in this context. Further studies are needed to confirm our findings.
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Tables and Figures Legends Table 1. Baseline Features possibly impacting on Prostate Cancer Diagnosis and/or Complications and Pain. Categorical variables reported as n (%); Continuous Variables reported as median (IQ range). DRE=Digital Rectal Examination; PCa=Prostate Cancer; UTI=Urinary Tract Infection; BPH=Benign Prostatic Hyperplasia; ‘’= calculated based on mpMRI prostate volume. *=aspirin use was not discontinued to perform the biopsies; ^=possibly influencing both complications, pain and PCa diagnostis. **= n=29 lesions found in n=25 external mpMRI not reviewed by institutional radiologists no Pi-RADS V2 score was assigned; ^*=missing for n=22 lesions. Table 2. Peri-procedural Outcomes, complications and functional outcomes Categorical variables reported as n (%); Continuous Variables reported as median (Interquartile Range). TR=Transrectal; AUR= acute urinary retention; UTI=Urinary Tract Infection; *= mean variation from before the procedure to 40 days after the procedure; °= n=1 indwelling catheter removed after 15 days – n=1 permanent indwelling catheter not successfully removed until subsequent surgical treatment; °°=indwelling catheter removed after 15 days; ^^=all were cases of mild fever <38-5°C; ‘’=selfresolving without antibiotics administration and being referred by the patient 2 days after the procedure; §§ = self-resolving with no antibiotics need and occurring on the day the procedure was performed. Supplementary Table 3. PCa detecion. ncs/csPCa= Non/Clinically Significant Prostate Cancer according to the START Criteria; *=csPCa identified either doing systematic cores or targeted cores (by one sampling type and not by the other).
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Supplementary Figure 1. Study Flowchart with excluded procedures and reason for exclusion. *=having a positive mpMRI; ‘’=no mpMRI being performed or negative mpMRI; y.o.=years old; Colostomy= colostomy not allowing biopsy and/or coagulation abnormalities; Coagulation=congenital coagulation pathologies or did not interrupt anticoagulants to undergo the procedure; ATB Prophilaxis= did not perform the antibiotic prophylaxis; Consent=did not provide written consent; Follow up=did not provide follow up data.
Figure 1. B=Bladder; P=Prostate; PA=Prostate Apex; PB=Prostate base; Pe=Perineum; PS=Pubic Symphisis; R=Rectum; an=anesthesia needle; bn=biopsy needle. A) Local anesthesia technique. Left: ultrasound image whilst performing lidocaine injection close to the posterior prostatic capsule (*=lidocaine pomphus) – Right: patient in the dorso-lithotomy position during local anesthesia needle insertion towards the posterior prostatic apex/capsule; local anesthesia is also administered in the subcutaneous planes (not shown in the Figure); B) Target cores. Left: Ultrasound image showing the target (light blue circle) and the biopsy needle before taking the core (bn) – Right: mpMRI sagittal T2 image previously overlapped with ultrasound images; D) Systematic cores scheme. Anterior quadrants and transition zone are not routinely biopsied (anterior biopsies are performed in case of suspicious mpMRI and/or suspicious ipo-echoic areas but not in case of negative mpMRI and/or systematic sampling). The technique does not involve the use of an introducer, with the perineal skin being punctured for each biopsy core taken. When performing systematic sampling the Bard needle is introduced: C.I) until the prostate inferior apical margin and then released to take the apical core; C.II) until halfway from the apex and the equator and then deployed to take the median cores; CIII) until halfway from the equator and the base and then deployed to take the basal cores; this scheme is repeated at the lateral and
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paramedian aspects of the prostate bilaterally; systematic cores are taken in posterior peripheral zone only.
Figure 2. A) Peri-procedural pain scores according to NRS in all the different procedural steps; B) Urinary and erectile function variations according to IPSS and IIEF-5 variations; C) Procedural timings. TR Probe= transrectal probe insertion; TPFBx=transperinal free-hand mpMRI targeted fusion biopsies; TPSBx=Transperineal free-hand systematic biopsies.
Conflict of interests: all authors have no conflict of interests to declare.
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Results of a multicenter study of 2115 patients. International journal of urology : official journal of the Japanese Urological Association. 2018 Sep 5:
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Table 1 – Baseline Features All mpMRI Targeted Systematic (TPFTBx) (TPSBx) n=459 n=279 n=180 Factors Possibly Influencing Complications and/or Pain BMI (Kg/m2) 25.4 (23.4-27.6) 25.1 (23.4-27.4) 25.9 (23.7-27.7) ASA Score 1 (1-2) 1 (1-2) 1 (1-2) Charlson Score 3 (2-3) 3 (2-3) 3 (2-4) Diabetes 42 (9.1) 26 (9.3) 16 (8.8) Immunosuppression drugs 14 (3.0) 5 (1.8) 9 (5.0) Antiplatelets Agents* 99 (21.6) 61 (21.9) 38 (21.1) Anticoagulants 19 (4.1) 8 (2.9) 11 (0.6) Neurological/Psychiatric Diseases 9 (2.0) 7 (2.5) 2 (1.1) Chronic Painkillers Use 4 (0.8) 1 (0.4) 3 (1.7) Ansiolitic Drugs 19 (4.1) 12 (4.3) 7 (3.8) Previous Prostatitis or UTI 73 (16.2) 42 (15.2) 31 (17.7) Factors Possibly Influencing PCa diagnosis/PSA levels Age (ys) 68 (62-73) 68 (61-72) 68 (62-73) PSA at biopsy (ng/mL) 6.5 (4.9-9.2) 6.4 (4.8-8.6) 6.6 (5.1-9.3) Suspicious DRE 171 (37.7) 100 (36.4) 71 (39.7) PCa Familiarity 67 (14.6) 38 (13.6) 29 (16.1) Race White 453 (98.7) 276 (98.9) 177 (98.3) Afroamerican 5 (1.1) 2 (0.7) 3 (1.7) Hyspanic 0 (0) 0 (0) 0 (0) Asian 1 (0.2) 1 (0.4) 0 (0) Number of cores taken^ 15 (12-15) 15 (15-16) 12 (12-12) Previous Biopsies 0 318 (69.3) 169 (60.6) 149 (82.8) 1 92 (20.0) 69 (24.7) 23 (12.8) ≥2 49 (10.7) 41 (14.7) 8 (4.4) Previous BPH Surgery Endoscopic 27 (5.9) 17 (6.1) 10 (5.6) Open 11 (2.4) 7 (2.5) 4 (2.2) BPH Treatment Alpha-litic 129 (28.1) 80 (28.7) 49 (27.2) 5-alpha reductase 14 (3.1) 8 (2.9) 6 (3.3) Both 16 (3.5) 7 (2.5) 9 (5.0) PDE-5 I 1 (0.2) 1(0.4) 0 (0) mpMRI features Lesions per patient 1 226 (81.0) 2 47 (16.8) ≥3 6 (2.2) Prostate volume (cc) 47.0 (34.1-61.6) Lesion volume (cc) 0.176 (0.086-0.438)
p
0.19 0.10 0.37 0.92 0.06 0.94 0.14 0.48 0.19 0.98 0.56 0.67 0.41 0.54 0.55
0.39 <0.001
<0.001 0.99 0.48
0.44
21
PSAd Pi-RADS V2 score
0.135 (0.094-0.210) 3 4 5 Missing**
54 (16.0) 215 (63.6) 40 (11.8) 29 (8.6)
1.5 T 1.5 T and endorectal coil 3T
263 (94.6) 14 (5.0) 1 (0.4)
mpMRI device
Table 1. Baseline Features possibly impacting on Prostate Cancer Diagnosis and/or Complications and Pain. Categorical variables reported as n (%); Continuous Variables reported as median (IQ range). DRE=Digital Rectal Examination; PCa=Prostate Cancer; UTI=Urinary Tract Infection; BPH=Benign Prostatic Hyperplasia; ‘’= calculated based on mpMRI prostate volume. *=aspirin use was not discontinued to perform the biopsies; ^=possibly influencing both complications, pain and PCa diagnostis. **= n=29 lesions found in n=25 external mpMRI not reviewed by institutional radiologists no Pirads V2 score was assigned; ^*=missing for n=22 lesions.
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Table 2. Peri-procedural Outcomes, complications and functional outcomes Categorical variables reported as n (%); Continuous Variables reported as median (Interquartile Range). TR=Transrectal; AUR= acute urinary retention; UTI=Urinary Tract Infection; *= mean variation from before the procedure to 40 days after the procedure; °= n=1 indwelling catheter removed after 15 days – n=1 permanent indwelling catheter not successfully removed until subsequent surgical treatment; °°=indwelling catheter removed after 15 days; ^^=all were cases of mild fever <38-5°C; ‘’=selfresolving without antibiotics administration and being referred by the patient 2 days after the procedure; §§ = self-resolving with no antibiotics need and occurring on the day the procedure was performed.
Table 2. Peri-procedural Outcomes, Complications and functional outcomes All mpMRI Targeted Systematic (TPFBx) (TPSBx) n=459 n=279 n=180 Procedural Timings (min) – median (IQR) Total 15 (12-20) 18 (15-22) 11 (9-13) Anesthesia 3 (2-4) 3 (2-4) 3 (3-5) Image Overlap 5 (3-7) Target cores 3 (2-5) Systematic cores 6 (4-8) 5 (4-6) 7 (6-9) Peri-procedural Pain (1 to 10 Numeric Rating Scale) – median (IQR) Pain max 5 (3-6) 5 (3-7) 5 (3-6) TR Probe 2 (1-4) 2 (1-4) 2 (1-4) Anesthesia 3 (2-5) 3 (2-5) 3 (2-5) Sampling 2 (1-4) 3 (1-5) 2 (1-4) Anxiety 3 (1-6) 3 (1-6) 3.5 (1-6) Functional Outcomes – mean (SD) IPSS variation (Δ)* 1.2 (2.1) 1.2 (2.2) 1.1 (1.8) IIEF-5 variation (Δ)* 1.1 (2.7) 0.9 (2.4) 1.2 (3.1) Complications – n (%) AUR 3 (0.6) 2 (0.7) 1 (0.6) Vasovagal Events 13 (2.8) 8 (2.9) 5 (2.8) Haematospermia 236 (54.0) 142 (54.2) 94 (53.7) duration (dys) 15 (7-28) 14.5 (5-21) 20 (10-30) Haematuria 316 (72.5) 191 (72.6) 125 (72.3) Duration (dys) 6 (3-10) 7 (3-10) 5.5 (3-10) Other bleeding 5 (1.2) 2 (0.8) 3 (1.7) UTI 0 (0) 0 (0) 0 (0) Fever 3 (0.7) 1 (0.4) 2 (1.1)
p <0.001 0.05
<0.001 0.20 0.99 0.40 0.03 0.32 0.61 0.25 0.88 0.97 0.85 <0.0001 0.91 0.52 0.38 0.4
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Figure 1
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Figure 2
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Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study Giancarlo Marra , Alessandro Marquis , Stefano Tappero , Daniele D’Agate , Marco Oderda , Giorgio Calleris , Marco Falcone , Riccardo Faletti , Luca Molinaro , Andrea Zitella , Laura Bergamasco , Paolo Gontero PII: DOI: Reference:
S0090-4295(20)30162-X https://doi.org/10.1016/j.urology.2019.11.078 URL 21979
To appear in:
Urology
Received date: Revised date: Accepted date:
24 July 2019 24 October 2019 12 November 2019
Please cite this article as: Giancarlo Marra , Alessandro Marquis , Stefano Tappero , Daniele D’Agate , Marco Oderda , Giorgio Calleris , Marco Falcone , Riccardo Faletti , Luca Molinaro , Andrea Zitella , Laura Bergamasco , Paolo Gontero , Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study, Urology (2020), doi: https://doi.org/10.1016/j.urology.2019.11.078
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Transperineal free-hand mpMRI fusion-targeted biopsies under local anesthesia: technique and feasibility from a single-centre prospective study Authors Giancarlo Marra1, Alessandro Marquis1, Stefano Tappero1, Daniele D’Agate1, Marco Oderda1, Giorgio Calleris1, Marco Falcone1, Riccardo Faletti2, Luca Molinaro3, Andrea Zitella1, Laura Bergamasco2 and Paolo Gontero1 1
Department of Urology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy 2
Department of Radiology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy 3
Department of Pathology, San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, Turin, Italy
Key words 1. Prostate 2. Prostate cancer 3. Prostate biopsy 4. Prostate fusion biopsy 5. Prostate mp-MRI targeted biopsy 6. Multi-parametric MRI of the prostate.
Corresponding author Dr. Alessandro Marquis e-mail: [email protected] Department of Urology San Giovanni Battista Hospital, Città della Salute e della Scienza and University of Turin, C.so Bramante 88/90 10126 Turin Italy Tel: +39 011 6336591 Fax: +39 011 6335707
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Abstract Objective: To evaluate the feasibility of ‘’in-office’’ TPFBx under LA. Materials and Methods: We prospectively screened for eligibility data of 724 consecutive men undergoing either TPFBx (target and systematic cores) or TPSBx (systematic cores only) from September 2016 to June 2018 due to suspicion of PCa, according to pre-defined exclusion criteria. Results: We included 459 men (TPFBx n=279 including n=338 mpMRI lesions, Pi-RADS 4 in 63.6%; TPSBx n=180). Median procedural time and maximum pain were 19 minutes and 5 NRS points; pain was highest at the time of LA. Only one major complication occurred (Clavien 3a). Haematuria and hematospermia were frequent (72.6% and 54.2%). Vaso-vagal reactions and AUR were rare (0.7% and 0.4%). No cases of UTI and one case of fever were recorded. No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx (p=0.86 and p=0.89). In comparison with TPSBx the sole differences were pain during prostatic sampling (p=0.03), duration of haematospermia (p<0.0001) and procedural time (p<0.001) all higher for TPFBx. csPCa was detected in n=150 (53.8%) patients in the TPFBx group (34.9%, 51.7% and 75% of Pirads 3,4 and 5 respectively). Addition of systematic cores detected n=25 csPCa that were missed by targeted cores (17.4% of all csPCa). Conclusions: TPFBx under LA are feasible, yielding high tolerability, low complications, no impact on erectile and urinary function and good csPCa detection. Addition of systematic to targeted cores remains recommended. Further studies are needed to confirm our findings.
Abbreviations PCa=Prostate Cancer mpMRI=multiparametric MRI Bx= biopsies TR=transrectal TP=transperineal TPFBx= transperineal free-hand mpMRI targeted fusion biopsies LA=local anesthesia TPSBx=Systematic transperineal free-hand biopsies csPCa=clinically significant prostate cancer
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1. Introduction After remaining largely unchanged for more than three decades, PCa diagnostic pathway has been revolutionized by mpMRI and mpMRI-targeted biopsies. Level 1 evidence now supports the use of mpMRI before prostate biopsy compared to the standard PSA and digital rectal exam based pathway alone [1-5]. However, several controversies remain, including the methods used to carry out the biopsies, whether in a cognitive, mpMRI in-bore or software-based fashion, the optimal number of targeted cores to be taken and the need of adding systematic cores to the targeted ones [3]. On the contrary, whether a prostate biopsy should be performed through the perineal or through the rectal route dates as far back as the nineties [6]. To date no clear answers in favor of one or the other approach are present and the debate enters unsolved the ‘’mpMRI-targeted biopsy era’’ [3, 7, 8]. On one hand, by avoiding the rectal route, TP Bx do not cause rectal bacteria inoculation in the prostate and may thus reduce infections. This is a major supporting argument for those favoring the TP approach in view of the alarming rise of quinolone-resistant bacteria at pre-biopsy rectal cultures and of post-biopsy sepsis-related complications [9, 10]. Some do also claim the TP route allows higher accessibility to certain areas of the prostate including apex, dorsolateral and anterior prostate segments, possibly resulting in higher PCa detection [3, 11]. On the other hand, those supporting the TR route argue for its higher deliverability in the outpatient setting, including: i) higher tolerability compared to TP, with many TP series reporting the use of general anesthesia; ii) lower comorbidity, especially in terms of urinary retention with some believing it more frequently occurs after TP Bx; iii) lower procedural timings [3].
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To our knowledge, no large prospective studies ever detailed the feasibility of TP mpMRI-targeted biopsies in an in-office setting [3]. Hence, we performed a prospective study to assess the feasibility of TP free-hand mpMRI targeted fusion biopsies under local anesthesia.
2. Methods 2.1 Study Outcomes and Outcome Measures Primary outcome was to assess the feasibility of TPFBx in terms of pain, peri- and post-procedural complications and urinary and erectile function changes. Secondary outcomes were: i) to validate TPFBx feasibility by comparing the results with systematic TP Bx, hypothesizing that adding targeted cores to systematic cores does not significantly impact on pain, peri- and post-procedural complications and urinary and erectile function; ii) csPCa detection rate of TPFBx.
2.2 Study Cohort and Data Collection From September 2016 to June 2018 we prospectively screened for study eligibility n=724 consecutive men undergoing either TPFBx (target cores and systematic cores) or TPSBx (systematic cores only) at San Giovanni Battista Hospital, Turin, Italy (ethical committee approval protocol 39636). Indications to perform Bx were: positive mpMRI (Pi-RADSV2 score≥3) performed due to elevated PSA and/or suspicious DRE - TPFBx; no mpMRI being performed or negative mpMRI with persistent PCa suspicion due to elevated PSA and/or suspicious DRE - TPSBx. Indications to mpMRI prior to Bx or following a previous negative Bx were at referring Urologist’s discretion. We ‘’a priori’’ excluded men with: i)PSA >20ng/mL; ii)age >80; iii)previous PCa diagnosis; iv)colostomy or rectal amputation; v)congenital coagulation alterations and/or who did not interrupt anticoagulant therapy (aspirin use was not discontinued at the time of Bx; patients 4
using anticoagulants or antiplatelet agents other than aspirin discontinued treatment or bridged with heparin depending on the risk deriving from therapy discontinuation); vi)no antibiotic prophylaxis; vii)no consent for study participation; viii)not providing follow up information. Study flowchart is represented in Supplementary Figure 1.
Data collection was performed at four different time frames: i)before the procedure (baseline features); ii)during the procedure (pain, peri-procedural complications and procedural timings); iii)immediately after the procedure, before patient discharge (early onset complications); iv)at 40 days from the biopsy during the first clinical follow-up visit (complications, functional outcomes and final pathological results).
Baseline features included detailed general and urological history and comorbidity status, evaluated using ASA score and Charlson Comorbidity Index. Urinary and erectile functions were assessed using IPSS and IIEF-5 respectively. Peri-procedural pain was determined using a 1 to 10 numeric rating scale -NRS. Complications were graded according to the Clavien-Dindo Score [12] and reported following the EAU Guidelines on reporting urological complications [13]. CsPCa was defined according to the START criteria [14].
3. Biopsy Technique (Figure 1) 2.3.1 Local Anesthesia All procedures were carried out in an in-office setting using the same LA technique. The patient is placed in the dorso-lithotomy position. Perineal skin is disinfected using a clorexidine solution. Under TRUS guidance 20cc (10cc per lobe) of lidocaine 1% are injected at the posterior prostate apex on the capsule surface. After peri-prostatic injection, while exiting the needle (without 5
further puncture), local anesthetic is also injected in perineal muscular planes, subcutaneous perineal planes and underneath the perineal skin, in the areas that will be subsequently traversed for the biopsy (Figure 1A).
2.3.2 Prostate Biopsy Oral ciprofloxacin was administered twice daily for three days starting the day before the procedure. Biopsies were collected using an 18-gauge, 22mm depth standard coaxial Bard needle (Bard, NJ, USA). Ultrasound images and fusion of ultrasound and mpMRI images was performed using the Esaote platform (EsaoteMyLab, NaviSuite5.0; Genova, IT), a rigid fusion platform allowing ‘’live’’ navigation and real-time monitoring of a correct overlap of ultrasound and mpMRI images and targets. The technique is detailed in Figure 1. First, when performing TPFBx, four cores per target are taken (Figure 1B). In case of patients’ movements causing target misalignment the procedure is interrupted to perform Ultrasound and mpMRI images fusion again before continuing the targeting. Subsequently, systematic cores are taken in the posterior and posterolateral prostate including a total of 12-cores (Figure 1C and 1D), with the anterior prostate quadrants and transition zone not being routinely biopsied (targeted biopsy of the anterior quadrants and transition zone is performed in case of suspicious mpMRI and/or suspicious ipo-echoic areas but not in case of negative mpMRI and/or systematic sampling). The technique did not involve the use of an introducer, with the perineal skin being punctured for each biopsy core taken and thus allowing: i) higher flexibility of the needle, especially in large prostates where possible
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interference with the pubic arch may be encountered; ii) less chance to conflict/interfere with the ultrasound probe.
3.1 mpMRI Imaging and Pathology We included both mpMRI performed at our center (n=149) or not (n=118). mpMRI protocol performed at our institution has been previously described [15]. All internal and n=93 external mpMRIs were reviewed by an experienced radiologist dedicated to prostate mpMRI and blind to clinical data using Pi-RADS V2 score and sectors [16]. All biopsy specimens were evaluated by a dedicated senior uro-pathologist.
2.5 Statistical Analysis Two open sources (www.openepi.com and www.vassarstats.net) and StatPlus:macLE v5.9.92 (Analyst Soft, CA, USA) were used. Continuous variables satisfying Kolmogorof-Smirnov/Lillienfor test and Shapiro Wilks W test were expressed as median (IQR) and compared using non-parametric Mann-Whitney test. Categorical variables were expressed as absolute numbers and/or percentages and compared using Chisquare or Fisher’s exact test when appropriate.
4. Results 4.1 Baseline Features Baseline features are shown in Table 1. Overall in the TPFBx group mean age and PSA were 68 years and 6.4 ng/mL respectively; 36.8% had equivocal DRE, 13.6% family history of PCa, 7.6% previous BPH surgery and 34% were taking medical BPH-treatments. Overall 338 lesions were identified in 279 men, the majority of which being Pi-RADS 4 (63.6%). 7
No major baseline differences were noted in factors potentially influencing complications, pain and PCa detection amongst TPFBx and TPSBx except number of previous biopsies and of cores taken, both higher for TPFBx (both p<0.001).
4.2 Peri-procedural outcomes Peri-procedural outcomes are displayed in Table 2 and Figure 2. Mean procedural time of TPFBx was 19.1 minutes, higher than TPSBx (p<0.001). The procedure was well tolerated with maximum experienced mean pain being 4.7 NRS points, with pain being highest at the time of LA and no patients discontinuing the procedure. No differences with TPSBx were noted with the exception of pain during prostatic sampling, slightly higher for TPFBx (p=0.03).
4.3 Complications Only one major complication occurred (Clavien 3a; AUR with permanent indwelling catheter until endoscopic treatment). Most frequent collateral event was haematuria, occurring in 72.6% and lasting a mean of 8.3 days, followed by haematospermia, occurring in 54.2% and lasting a mean of 15.3 days. Eight men experienced post-procedural vaso-vagal reactions. Two patients who were already scheduled for BPH surgery before the procedure had AUR. No cases of UTI and one case of fever, self-resolving without antibiotics administration and being referred by the patient two days after the procedure were recorded. No significant complications differences were noted with TPSBx, with the exception of longer duration of haematospermia (p<0.0001).
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4.4 Impact on erectile and urinary function No significant changes in erectile and urinary functions were noted from baseline compared to 40 days after TPFBx with mean IPSS and IIEF-5 variations being -1.2 (p=0.86) and -0.9 (p=0.89) respectively. Similarly, no major differences were noted in the TPSBx group (IPSS p=0.9; IIEF-5 p=0.66).
4.5 Detection Rate (Supplementary Table 1) csPCa was detected in n=150 (53.8%) patients in the TPFBx group (34.9%, 51.7% and 75% of Pirads 3,4 and 5 respectively), with Gleason score 7 in the majority of the cases (84%). In the TPSBx group csPCa was detected in n=81 (45%). Addition of systematic cores detected n=25 csPCa that were missed by targeted cores (17.4% of all csPCa).
5. Discussion To our knowledge, this is the largest study to prospectively evaluate TPFBx under LA from a 360degree perspective, including complications, procedural timings, impact on erectile and urinary function and PCa detection. Overall, TP freehand sampling being performed using an mpMRI targeted and/or systematic technique proved feasible and safe in an in-office setting using LA and yielded acceptable PCa detection. The addition of targeted to systematic cores did not significantly impact on overall pain, complications, urinary and erectile function. Several aspects of our work are of relevance. On one hand our results constitute a helpful tool for patient counselling before TP biopsies. On the other hand, the present study places itself amongst the growing body of evidence in support of TPFBx under LA use, strengthening the evidence of very recent reports [3, 7, 17]. 9
First, pain is low showing a high tolerability and no patients interrupted the procedure due to perceived pain. As found by others [7, 17], the highest degree of pain is experienced at the time of LA. Contrarily, sampling is less painful being slightly worse than ultrasound probe rectal insertion. These findings are confirmed by the comparison of TPFBx and TPSBx: as the highest pain scores are recorded during the anesthesia, no major differences in maximum perceived pain were recorded (p=0.2). When assessing sampling alone, the increased number of cores deriving from the addition of targets, and probably the longer procedural timings of TPFBx, resulted in pain increase (p=0.03). However, we do believe the one point NRS difference compared to TPSBx as not being clinically meaningful. Furthermore, this difference did not translate into any dissimilarity in the maximum perceived pain. Second, despite others reported longer procedural timings, the procedure is relatively fast, generally lasting less than 20 minutes [17]. Our institutional experience with TP LA sampling, which also became the standard Bx technique since 2013 may partly explain this difference. Third, complications are low, generally reflecting previous findings of TP and TR series [19, 20]. Bleeding was extremely rare so as for vaso-vagal reactions which did not hamper the accomplishment of the biopsy. Hematuria and hematospermia occurred frequently. Nonetheless, all these events were self-resolving. Urinary retention and infectious complications deserve a separate mention. Despite no RCT ever showed any difference between the transrectal and transperineal routes [21], they are usually considered amongst major drawbacks and advantages of TP biopsies respectively [3]. Concerning retention, its incidence in TP series varies widely, being described in up to 24% of men [19, 20]. However, studies with higher retention rates are usually those performing template mapping approaches where 1 core is taken every 2-3cc of the gland reaching up to 100 cores in large prostates. Also, these procedures are performed under general anesthesia which is another 10
precipitating factor favoring retention. As noted by others [7, 19, 20, 22], in our series retention was rare, occurring in less than 1%. Furthermore, the three retention cases were men already scheduled to undergo BPH surgery. Hence, although it may occur, when using up to 18 TP cores and a LA technique, retention is negligible and comparable to the TR approach [19, 20]. Moreover, no significant alteration in urinary symptoms was noted at 40 days. Although some degree of local edema is well-known to occur following biopsies, it is unlikely to significantly affect micturition, at least from the patient perspective. As for infections, no cases of UTI and uro-sepsis were recorded. Fever, when it occurred, may have been unrelated to the biopsy as it self-resolved with no additional antibiotic needs in maximum 3 days after the procedure together with flu-like symptoms. This is no surprise and confirms the extremely low infectious risk of the TP route [23]. Meyer et al just published the results of the first 43 men undergoing ‘’antibiotic free’’ TP prostate biopsy in the US, describing no infectious cases [8]. In our series we used quinolones as antibiotic prophylaxis. As one in five to almost one in two men harbors quinolones resistant bacteria at pre-biopsy rectal culture [3, 10] our results support decreasing antibiotic needs when using the TP route. Given the alarming increase world-wide of post-procedural fever, hospital re-admission and sepsis following TR biopsies [9, 19] several groups suggested upfront antibiotic augmentation [10, 24]. Recently, two studies even assessed carbapenem-based prophylaxis [25, 26]. In our view diminishing infectious rates in the short term using third-line antibiotics does not seem the correct answer to the global warning on antibiotic abuse and will likely further increase resistance [27]. From an infectious perspective, although no RCT do exist proving TP superiority, we favor this approach over the TR. Fourth, in line with previous studies, we confirmed no impact on erectile function. Despite periprostatic nerve block and edema of neurovascular bundles have been suggested as possible 11
mechanisms altering erections, even in case they occur immediately after the procedure, they do not cause any significant nor permanent variations on a longer term [19, 20]. Fifth, detection of csPCa is promising, being in line with recently published multicenter series and trials [1, 4, 5, 28] and does not seem to be hampered in an in-office LA setting. Interestingly, we did find exceedingly high and low proportions of csPCA and ncsPCa respectively, which were confirmed by the pathological review, mainly related to the low incidence of low volume Gleason Score 6 in our series. It remains unclear whether this derives from the TP approach and it certainly warrants further investigation. Importantly, our study was not designed to estimate potential advantages of mpMRI targeting as the benefits of the mpMRI-based pathway are no more a matter of debate [1, 4, 5]. Furthermore, by including both primary and secondary biopsy settings and external mpMRIs being performed with different protocols, our cancer detection does not refer to a specific patient group. Oncological outcomes were not a primary endpoint and were reported to allow an acknowledgment of technique results. Nonetheless, we found approximately one on five men having csPCa would have been missed by targeted cores, if not performing systematic sampling. Given the overall low morbidity and complications rate, our findings support the addition of systematic to targeted cores when performing TPFBx under LA [4, 5, 28]. The single center nature of the present work requires others to reproduce our findings. We are currently performing a multicenter study in collaboration with other centers and results update has been planned in the near future to confirm the feasibility of TPFBx in an in-office setting and to expand their use.
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6. Conclusions Transperineal mpMRI-targeted biopsies under LA are feasible, yielding high tolerability, low complications with negligible urinary retention and infectious risks, no impact on erectile and urinary function and good csPCa detection in an ‘’in-office’’ setting. The addition of systematic to targeted cores remains recommended in this context. Further studies are needed to confirm our findings.
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Tables and Figures Legends Table 1. Baseline Features possibly impacting on Prostate Cancer Diagnosis and/or Complications and Pain. Categorical variables reported as n (%); Continuous Variables reported as median (IQ range). DRE=Digital Rectal Examination; PCa=Prostate Cancer; UTI=Urinary Tract Infection; BPH=Benign Prostatic Hyperplasia; ‘’= calculated based on mpMRI prostate volume. *=aspirin use was not discontinued to perform the biopsies; ^=possibly influencing both complications, pain and PCa diagnostis. **= n=29 lesions found in n=25 external mpMRI not reviewed by institutional radiologists no Pi-RADS V2 score was assigned; ^*=missing for n=22 lesions. Table 2. Peri-procedural Outcomes, complications and functional outcomes Categorical variables reported as n (%); Continuous Variables reported as median (Interquartile Range). TR=Transrectal; AUR= acute urinary retention; UTI=Urinary Tract Infection; *= mean variation from before the procedure to 40 days after the procedure; °= n=1 indwelling catheter removed after 15 days – n=1 permanent indwelling catheter not successfully removed until subsequent surgical treatment; °°=indwelling catheter removed after 15 days; ^^=all were cases of mild fever <38-5°C; ‘’=selfresolving without antibiotics administration and being referred by the patient 2 days after the procedure; §§ = self-resolving with no antibiotics need and occurring on the day the procedure was performed. Supplementary Table 3. PCa detecion. ncs/csPCa= Non/Clinically Significant Prostate Cancer according to the START Criteria; *=csPCa identified either doing systematic cores or targeted cores (by one sampling type and not by the other).
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Supplementary Figure 1. Study Flowchart with excluded procedures and reason for exclusion. *=having a positive mpMRI; ‘’=no mpMRI being performed or negative mpMRI; y.o.=years old; Colostomy= colostomy not allowing biopsy and/or coagulation abnormalities; Coagulation=congenital coagulation pathologies or did not interrupt anticoagulants to undergo the procedure; ATB Prophilaxis= did not perform the antibiotic prophylaxis; Consent=did not provide written consent; Follow up=did not provide follow up data.
Figure 1. B=Bladder; P=Prostate; PA=Prostate Apex; PB=Prostate base; Pe=Perineum; PS=Pubic Symphisis; R=Rectum; an=anesthesia needle; bn=biopsy needle. A) Local anesthesia technique. Left: ultrasound image whilst performing lidocaine injection close to the posterior prostatic capsule (*=lidocaine pomphus) – Right: patient in the dorso-lithotomy position during local anesthesia needle insertion towards the posterior prostatic apex/capsule; local anesthesia is also administered in the subcutaneous planes (not shown in the Figure); B) Target cores. Left: Ultrasound image showing the target (light blue circle) and the biopsy needle before taking the core (bn) – Right: mpMRI sagittal T2 image previously overlapped with ultrasound images; D) Systematic cores scheme. Anterior quadrants and transition zone are not routinely biopsied (anterior biopsies are performed in case of suspicious mpMRI and/or suspicious ipo-echoic areas but not in case of negative mpMRI and/or systematic sampling). The technique does not involve the use of an introducer, with the perineal skin being punctured for each biopsy core taken. When performing systematic sampling the Bard needle is introduced: C.I) until the prostate inferior apical margin and then released to take the apical core; C.II) until halfway from the apex and the equator and then deployed to take the median cores; CIII) until halfway from the equator and the base and then deployed to take the basal cores; this scheme is repeated at the lateral and
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paramedian aspects of the prostate bilaterally; systematic cores are taken in posterior peripheral zone only.
Figure 2. A) Peri-procedural pain scores according to NRS in all the different procedural steps; B) Urinary and erectile function variations according to IPSS and IIEF-5 variations; C) Procedural timings. TR Probe= transrectal probe insertion; TPFBx=transperinal free-hand mpMRI targeted fusion biopsies; TPSBx=Transperineal free-hand systematic biopsies.
Conflict of interests: all authors have no conflict of interests to declare.
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Table 1 – Baseline Features All mpMRI Targeted Systematic (TPFTBx) (TPSBx) n=459 n=279 n=180 Factors Possibly Influencing Complications and/or Pain BMI (Kg/m2) 25.4 (23.4-27.6) 25.1 (23.4-27.4) 25.9 (23.7-27.7) ASA Score 1 (1-2) 1 (1-2) 1 (1-2) Charlson Score 3 (2-3) 3 (2-3) 3 (2-4) Diabetes 42 (9.1) 26 (9.3) 16 (8.8) Immunosuppression drugs 14 (3.0) 5 (1.8) 9 (5.0) Antiplatelets Agents* 99 (21.6) 61 (21.9) 38 (21.1) Anticoagulants 19 (4.1) 8 (2.9) 11 (0.6) Neurological/Psychiatric Diseases 9 (2.0) 7 (2.5) 2 (1.1) Chronic Painkillers Use 4 (0.8) 1 (0.4) 3 (1.7) Ansiolitic Drugs 19 (4.1) 12 (4.3) 7 (3.8) Previous Prostatitis or UTI 73 (16.2) 42 (15.2) 31 (17.7) Factors Possibly Influencing PCa diagnosis/PSA levels Age (ys) 68 (62-73) 68 (61-72) 68 (62-73) PSA at biopsy (ng/mL) 6.5 (4.9-9.2) 6.4 (4.8-8.6) 6.6 (5.1-9.3) Suspicious DRE 171 (37.7) 100 (36.4) 71 (39.7) PCa Familiarity 67 (14.6) 38 (13.6) 29 (16.1) Race White 453 (98.7) 276 (98.9) 177 (98.3) Afroamerican 5 (1.1) 2 (0.7) 3 (1.7) Hyspanic 0 (0) 0 (0) 0 (0) Asian 1 (0.2) 1 (0.4) 0 (0) Number of cores taken^ 15 (12-15) 15 (15-16) 12 (12-12) Previous Biopsies 0 318 (69.3) 169 (60.6) 149 (82.8) 1 92 (20.0) 69 (24.7) 23 (12.8) ≥2 49 (10.7) 41 (14.7) 8 (4.4) Previous BPH Surgery Endoscopic 27 (5.9) 17 (6.1) 10 (5.6) Open 11 (2.4) 7 (2.5) 4 (2.2) BPH Treatment Alpha-litic 129 (28.1) 80 (28.7) 49 (27.2) 5-alpha reductase 14 (3.1) 8 (2.9) 6 (3.3) Both 16 (3.5) 7 (2.5) 9 (5.0) PDE-5 I 1 (0.2) 1(0.4) 0 (0) mpMRI features Lesions per patient 1 226 (81.0) 2 47 (16.8) ≥3 6 (2.2) Prostate volume (cc) 47.0 (34.1-61.6) Lesion volume (cc) 0.176 (0.086-0.438)
p
0.19 0.10 0.37 0.92 0.06 0.94 0.14 0.48 0.19 0.98 0.56 0.67 0.41 0.54 0.55
0.39 <0.001
<0.001 0.99 0.48
0.44
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PSAd Pi-RADS V2 score
0.135 (0.094-0.210) 3 4 5 Missing**
54 (16.0) 215 (63.6) 40 (11.8) 29 (8.6)
1.5 T 1.5 T and endorectal coil 3T
263 (94.6) 14 (5.0) 1 (0.4)
mpMRI device
Table 1. Baseline Features possibly impacting on Prostate Cancer Diagnosis and/or Complications and Pain. Categorical variables reported as n (%); Continuous Variables reported as median (IQ range). DRE=Digital Rectal Examination; PCa=Prostate Cancer; UTI=Urinary Tract Infection; BPH=Benign Prostatic Hyperplasia; ‘’= calculated based on mpMRI prostate volume. *=aspirin use was not discontinued to perform the biopsies; ^=possibly influencing both complications, pain and PCa diagnostis. **= n=29 lesions found in n=25 external mpMRI not reviewed by institutional radiologists no Pirads V2 score was assigned; ^*=missing for n=22 lesions.
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Table 2. Peri-procedural Outcomes, complications and functional outcomes Categorical variables reported as n (%); Continuous Variables reported as median (Interquartile Range). TR=Transrectal; AUR= acute urinary retention; UTI=Urinary Tract Infection; *= mean variation from before the procedure to 40 days after the procedure; °= n=1 indwelling catheter removed after 15 days – n=1 permanent indwelling catheter not successfully removed until subsequent surgical treatment; °°=indwelling catheter removed after 15 days; ^^=all were cases of mild fever <38-5°C; ‘’=selfresolving without antibiotics administration and being referred by the patient 2 days after the procedure; §§ = self-resolving with no antibiotics need and occurring on the day the procedure was performed.
Table 2. Peri-procedural Outcomes, Complications and functional outcomes All mpMRI Targeted Systematic (TPFBx) (TPSBx) n=459 n=279 n=180 Procedural Timings (min) – median (IQR) Total 15 (12-20) 18 (15-22) 11 (9-13) Anesthesia 3 (2-4) 3 (2-4) 3 (3-5) Image Overlap 5 (3-7) Target cores 3 (2-5) Systematic cores 6 (4-8) 5 (4-6) 7 (6-9) Peri-procedural Pain (1 to 10 Numeric Rating Scale) – median (IQR) Pain max 5 (3-6) 5 (3-7) 5 (3-6) TR Probe 2 (1-4) 2 (1-4) 2 (1-4) Anesthesia 3 (2-5) 3 (2-5) 3 (2-5) Sampling 2 (1-4) 3 (1-5) 2 (1-4) Anxiety 3 (1-6) 3 (1-6) 3.5 (1-6) Functional Outcomes – mean (SD) IPSS variation (Δ)* 1.2 (2.1) 1.2 (2.2) 1.1 (1.8) IIEF-5 variation (Δ)* 1.1 (2.7) 0.9 (2.4) 1.2 (3.1) Complications – n (%) AUR 3 (0.6) 2 (0.7) 1 (0.6) Vasovagal Events 13 (2.8) 8 (2.9) 5 (2.8) Haematospermia 236 (54.0) 142 (54.2) 94 (53.7) duration (dys) 15 (7-28) 14.5 (5-21) 20 (10-30) Haematuria 316 (72.5) 191 (72.6) 125 (72.3) Duration (dys) 6 (3-10) 7 (3-10) 5.5 (3-10) Other bleeding 5 (1.2) 2 (0.8) 3 (1.7) UTI 0 (0) 0 (0) 0 (0) Fever 3 (0.7) 1 (0.4) 2 (1.1)
p <0.001 0.05
<0.001 0.20 0.99 0.40 0.03 0.32 0.61 0.25 0.88 0.97 0.85 <0.0001 0.91 0.52 0.38 0.4
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Figure 1
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Figure 2
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