Local versus general anesthesia transperineal prostate biopsy: Tolerability, cancer detection, and complications

Abstract Objectives To compare data on transperineal template biopsy (TPTB) under general anesthesia (GA) compared with local anesthesia (LA) procedures using the PrecisionPoint™ Transperineal Access System (PPTAS) in relation to tolerability, cancer detection rate, complications, and cost. Methods A prospective pilot cohort study of patients undergoing transperineal biopsy was performed. Patients were excluded if they had concurrent flexible cystoscopy or language barriers. Patients had a choice of GA or LA. A prospective questionnaire on Days 0, 1, 7, and 30 was applied. The primary outcome was patient tolerability. Secondary outcomes were cancer detection rate, complication rate, and theater utilization. Results This study included 80 patients (40 GA TPTB and 40 LA PPTAS). Baseline characteristics including age, prostate‐specific antigen (PSA), digital rectal examination (DRE), findings, and prostate volume were comparable between the groups (p = 0.3790, p = 0.9832, p = 0.444, p = 0.3939, respectively). Higher median prostate imaging‐reporting and data system (PI‐RADS) score of 4 (interquartile range [IQR] 2) versus 3 (IQR 1) was noted in the LA group (p = 0.0326). Pain was higher leaving recovery in the GA group however not significantly (p = 0.0555). Median pain score at LA infiltration was 5/10 (IQR 3), with no difference in pain at Days 1, 7, or 30 (p = 0.2722, 0.6465, and 0.8184, respectively). For GA versus LA, the overall cancer detection rate was 55% versus 55% (p = 1.000) with clinically significant cancer in 22.5% versus 35% (p = 0.217). Acute urinary retention (AUR) occurred in 5% of GA and 2.5% of LA patients (p = 1.000). The GA cohort spent longer in theater and in recovery with a median of 93.5 min versus 57 min for the LA group (p = <0.0001). Conclusion This study demonstrates that transperineal biopsy is safely performed under LA with no difference between the cohorts in relation cancer detection or AUR. LA biopsy also consumed less theater and recovery resources. A further larger prospective randomized controlled trial is required to confirm the findings of this study.


| INTRODUCTION
There have been several advances in prostate biopsy for the diagnosis of prostate cancer (PCa) in recent years. 1 Internationally greater than 95% of prostate biopsies were performed using the transrectal route in 2018. 2 There are several disadvantages of prostate biopsy using the transrectal route. Most importantly, it is associated with a 2%-3% rate of urosepsis which carries significant morbidity and mortality. 3 Furthermore, studies have demonstrated that transrectal ultrasound guided (TRUS) prostate biopsies perform poorly in the detection of anterior zone lesions and have a lower cancer detection rate than transperineal prostate biopsies (TPBx). 4 In the last decade, many institutions have changed practice to replace transrectal biopsy with TPBx in a move that has been dubbed by some as "TRexit." 1 Currently in the United Kingdom, 32.8% of biopsies are performed via the transperineal route. 5 Since the introduction of TRUS biopsy, a major concern has been that of infection, specifically severe febrile urinary tract infection (UTI). 3 This can lead to bacteraemia, urosepsis, septic shock, and multi-organ dysfunction requiring intensive care support. 3 An increased prevalence of multiresistant organisms including extendedspectrum β-lactamase (ESBL) and quinolone resistant organisms has been reported in recent years relating to TRUS biopsy sepsis. 6,7 This has resulted in broad-spectrum carbapenems being used in patients preprocedure and postprocedure. 3 With the introduction of TPBx, there has been a drastic reduction in the rates of procedure-related infection. 8 Compared with TPBx, UTI is 5.4 times more common when TRUS biopsy is performed, with further increased risk if greater than 12 cores are sampled. 2 A systematic review including 6609 patients found that only 5 (0.076%) patients undergoing TPBx required re-admission to hospital for treatment of sepsis. 3 These rates are 40 to 70 times lower than those seen with TRUS biopsy. 3 This has a significant financial impact on the healthcare system with a reported cost of AUD$7362 per sepsis related admission. 9 Transperineal template biopsy (TPTB) using a prostate mapping technique has been shown to have a higher detection rate for malignancy, as well as showing a lower rate of postoperative infection and sepsis. 2 In the past TPTB has been reserved for use in patients on AS undergoing confirmatory biopsy or those with a rising PSA and negative TRUS biopsy. 10 This has been mainly due to the economic impact it has with relation to the need for general anesthesia (GA), equipment, and increased procedure time. In recent years, technological advances have allowed for the performance of TPBx under local anesthesia (LA). 11 The PrecisionPoint™ Transperineal Access System (PPTAS) (Corbin Clinical Resources, MD, USA) gained Food and Drug Administration (FDA) approval in 2016. 12 This system reduces the number of perineal skin punctures to just two as well as removing the requirement for an exaggerated lithotomy position, overall improving patient comfort, and allowing for procedures to be performed under LA only. To our knowledge, there has not been any prospective study directly comparing the outcomes of LA TPBx versus GA TPTB. This is a pilot prospective study that aims to compare the rates of cancer detection, tolerability, as well as patient satisfaction between GA TPTB and LA TPBx using the PPTAS. This study also aims to assess the economic viability of the procedure using surrogate markers for resource consumption.

| METHODS
This is a prospective single center pilot cohort study. The inclusion criteria were all patients undergoing TPBx at our institution from February 2020 to September 2020. Patients who had concurrent procedures such as flexible cystoscopy were excluded to avoid confounding factors affecting the outcomes of this study. Non-English-speaking patients, as defined by the hospital admission information, were excluded. This was in relation to the process of reading and understanding the consent and study participant information as well as feasibility for follow-up phone calls. There were five patients excluded due to language barriers. Patients who met the inclusion and exclusion criteria were given time to read the patient information sheet and were consented for participation in this study. No patients declined to participate in the study. As this is a cohort study, enrolment in the LA versus GA TPBx arm of the study was based on patient preference after informed consent and pre-operative discussion with patients regarding the risk versus benefits of prostate biopsy performed under LA versus GA. Patients who initially underwent LA TPBx but needed a conversion to GA were not included in the final data analysis but were captured to determine the rate of conversion to GA. As this was a pilot study, sample size calculations were not performed. The study aimed to enroll 80 patients (40 LA PPTAS and 40 GA TPTB).
Prior to the procedure, patients were asked to rate their pain on a numeric rating scale (NRS) numbered 0-10 with 0 being "No pain" and 10 being "Worst pain," Pain scores were assessed at eight time points: pre-operatively, LA infiltration, ultrasound probe insertion, biopsy gun firing, leaving recovery, Day 1 (retrospectively during the Day 7 phone call), Day 7, and Day 30. All patients were given a day of surgery questionnaire as well as postoperative phone call questionnaires on Days 7 and 30. A copy of this questionnaire is available in the supporting information.
Clinicopathological data were collected from hospital electronic medical records and included demographic information; age, date of biopsy, prostate-specific antigen (PSA), comorbidities, digital rectal examination (DRE) findings, multiparametric magnetic resonance imaging (mpMRI) prostate imaging-reporting and data system (PI-RADS) score, prostate volume, number of cores taken, and Fisher's exact test of independence was used to determine associations between categorical variables given the small sample size. A two-sided p-value <0.05 was considered statistically significant.

| Biopsy technique
Two transperineal biopsy approaches, LA PPTAS and GA TPTB, were used in this study. All procedures were carried out in the day procedure setting. All patients were prescribed 400-mcg Tamsulosin for The threshold for conversion to GA was relatively low to avoid unnecessary patient discomfort. If a patient did not tolerate a DRE on table or did not tolerate the insertion of the local anesthetics needle, they were converted to GA.
GA TPTB-Patients were placed in high lithotomy position. Template biopsies utilized the brachytherapy 5-mm grid/stepper unit (Enovare, PA, USA). Administration of local anesthetic (approximately 20 ml of 0.75% Ropivocaine) to achieve a pudendal nerve block on completion of the procedure was dependent on surgeon preference. respectively. There was no significant difference between the cohorts as to whether patients were having a primary biopsy, repeat biopsy after a negative biopsy, or on active surveillance (p = 0.122). The patient characteristics pre-operatively are summarized in Table 1 and statistically significant differences are highlighted in bold. The only statistically significant difference between the groups at baseline related to PI-RADS score where the LA PPTAS group had a higher median score (p = 0.0326).

| RESULTS
At baseline there was a higher median NRS pain score seen in the LA PPTAS (p = 0.0080). Using the NRS to evaluate pain postoperatively, the score was not different between the groups on Day 1 (p = 0.1783), Day 7 (p = 0.2202), or Day 30 (p = 0.5686). At the time of leaving the recovery area patients in the GA TPTB group tended to have more pain compared with the LA PPTAS group, but this did not reach the threshold for significance (p = 0.0555). When assessing patients return to work following the procedure, there were 38 patients in employment at the time. Of these 81.5% (n = 31) returned to work within 7 days of the procedure. Patients who had an LA procedure returned to work significantly faster than those who had a GA (p = 0.0459). This is summarized in Table 2 below and statistically significant differences are highlighted in bold.
In the LA PPTAS group 90% (n = 36) reported they would be happy to have this procedure performed again if necessary. Similarly, 97.5% of patients in the GA TPTB group would have the same procedure again (p = 0.359). There were two patients (4.8%; n = 2/42) excluded from the study who did not tolerate LA infiltration and required conversion to GA biopsy in the study period. Of the 9 patients in the LA group versus the 8 patients in the GA group who had had a previous GA TPTB; 22.2% (n = 2) versus 37.5% (n = 3) preferred the current procedure, 55.6% (n = 5) versus 50% (n = 4) felt it was comparable to their previous procedure, and 22.2% (n = 2) versus 12.5% (n = 1) felt it was worse than their previous procedure.
In the LA PPTAS group the overall rate of cancer detection was 55% (n = 22). The rate of csPCa ISUP≥2 was 35% (n = 14). For patients undergoing primary biopsy (n = 31), the cancer detection rate overall was 48.3% (n = 15) and for csPCa was 35.5% (n = 11). There was no statistically significant difference between the two groups when assessing overall cancer detection rate (p = 1.000). The median number of cores taken in the GA TPTB cohort was 27 (IQR 8), compared with 33 (IQR 21.5) in the LA PPTAS cohort (p = 0.0084).  Acute urinary retention (AUR) requiring catheterization occurred in 5% (n = 2) of patients in the GA cohort compared with 2.5% (n = 1) of the LA cohort (p = 1.000). The episode of AUR in the LA group occurred Day 9 postoperatively and was associated with urosepsis secondary to gram-negative bacteraemia requiring catheterization and intravenous antimicrobial therapy. The patient presented with urinary retention followed by fever but remained haemodynamically stable through the entire episode and only required ward-based management.
Culture positive symptomatic UTI occurred in 0% of the GA group and in 5% (n = 2) of the LA group (p = 0.494). One patient in the GA group was treated with oral antibiotics in the community for dysuria postprocedure; however, his urine sample was sterile. Nonelective readmission occurred in 2.5% (n = 1) of the GA cohort compared with 5% (n = 2) of the LA cohort (p = 0.494). All complications that occurred were classified as Clavien-Dindo ≤2.
There was no difference in procedure specific time between the cohorts (p = 0.5292). When anesthetic (local or general) time was included, the GA TPTB cohort had a significantly longer time in theater (p < 0.0001). The time the patient was in the theater department from the beginning of the procedure to leaving recovery was significantly shorter in the LA PPTAS group (p < 0.0001). Men in the LA PPTAS group spent a significantly shorter period in the recovery area after the procedure (p < 0.0001). A summary of the times can be found in Table 3 and statistically significant differences are highlighted in bold.

| DISCUSSION
In recent years there has been a shift towards the TP route for pros- This study demonstrates that LA TPBx is well tolerated with 95.2% of patients able to complete the procedure. The 4.8% rate of conversion to GA is consistent with previous studies on LA TPBx. 16,17 Kum et al. previously reported LA injection to be the most painful part of the LA TPBx procedure. 16 The authors in this study had a similar experience, and this present study showed that the pain score during LA injection to be manageable with a median of 5 (IQR 3) on the NRS.
The pain score recorded for ultrasound probe insertion ( study is therefore the first to demonstrate that PPTAS cancer detection rates are not inferior to TPTB (p = 1.000). A recently published study looking at 174 standard grid-based biopsy patients compared with 304 freehand biopsy patients has shown an equivalent cancer detection rate between both techniques. 22 In the first 7 days following the procedure, there were no documented new infections in either group, indicating that there was no introduction of bacteria via the needle biopsy. This is consistent with previous literature and supports the adoption of the TP route rather than the TR route as a safer method of biopsy by avoiding fecal contamination. 2,3,8 Unfortunately, there was an infectious complication relating to a patient suffering from AUR on day 9 following the operation. This patient was re-admitted to hospital and treated with antimicrobial therapy for gram-negative bacteraemia. The patient had a single recorded fever, did not exhibit any hemodynamic changes, nor require any inotropic support. The patient recovered uneventfully.
Although this is secondary to the AUR and not related to the introduction of bacteria into the prostate via the needle biopsy, it remains an infectious complication following the procedure. The second patient recorded as an infection was symptomatic for a UTI prior to biopsy and was commenced on antimicrobial therapy at the time of biopsy. However, the overall rate of infection remains low at 5% (n = 2) and is in keeping with other PPTAS studies. 16  Given the PPTAS device is new to the surgeons involved, it is anticipated that the procedure time will decrease with increasing experience of the device. In further studies, precise and comprehensive costing per patient will be obtained.

| Limitations
This study has a relatively small sample size due to the nature of it being a pilot study. As such, the study may be underpowered to detect differences in outcomes such as cancer detection rates and complication rates. However, even at this small number, this study detected a difference in the postoperative pain score, as well as a significant difference in use of theater resources between the two techniques.
Participants were not randomly allocated to the method of biopsy and instead chose themselves whether to have GA or LA. The selection bias may have affected outcomes such as pain scores and conversion rate to GA. However, this is representative of real-life scenario where all patients would require informed consent prior to proceeding with any procedure. Selection bias through the exclusion of non-English speaking patients has also been noted; however, given the small number of patients this excluded, it is not thought that this is significant. Furthermore, the authors of this study aim to conduct further prospective randomized controlled trials in the future based on the results of this pilot study, which will endeavor to control for this possible bias.
Lack of standardization of technique due to multiple surgeons being involved may be another confounding factor. There are no clear guidelines in relation to the use of antimicrobial agents pre-operatively, the use of pudendal nerve block postoperatively, or the number of cores required, and each varies widely depending on surgeon preference. These factors may have influenced some outcome measures such as cancer detection, pain scores, and complication rates. However, this also represents real-world scenario where surgeons vary slightly in their techniques and practices.

| CONCLUSION
This prospective pilot cohort study demonstrates that LA TPBx is safe, effective, and tolerable. The pain score given for the maximum discomfort point of the procedure was a median of 5/10. The total operative time including anesthesia was shorter in the LA PPTAS group, and patients spent a shorter time in recovery after the LA procedure. This reduction in time saves theater resources and will allow a higher number of patients to be biopsied at any given time.
Given these findings, a precise cost comparison of these procedures is required to investigate financial viability, especially given the aging population and the foreseen increase in the prevalence of PCa. Further studies to confirm the findings of this pilot study are warranted.

ACKNOWLEDGMENTS
None to declare.

CONFLICT OF INTERESTS (ICMJE DISCLOSURE)
We confirm that this paper has not been published or submitted for publication elsewhere and that all authors have contributed significantly and are all in agreement with the content of the manuscript.
The following apply to all listed authors: • All support for the present manuscript (e.g., funding, provision of study materials, medical writing, and article processing charges): none • Grants or contracts from any entity: none