Prostate cancer (PCa) remains the second most common malignancy in men worldwide, with over 1.4 million new diagnoses annually [1]. The cornerstone of diagnosis remains histologic sampling of the prostate gland, typically triggered by an elevated serum prostate-specific antigen (PSA) level or an abnormal digital rectal examination (DRE). For nearly three decades, the transrectal ultrasound-guided (TRUS) biopsy has been the standard of care due to its convenience, speed, and ability to be performed in an office setting under local anesthesia. The typical TRUS procedure involves passing a biopsy needle through the rectal wall into the prostate, often after a periprostatic nerve block. While generally well-tolerated, this approach carries an inherent and increasingly problematic risk: infectious complications. The risk of infection following TRUS biopsy arises from the unavoidable translocation of enteric bacteria, most commonly Escherichia coli and Klebsiella species, from the rectal lumen into the prostatic tissue and bloodstream. Even with pre-procedural rectal cleansing and prophylactic antibiotics, the reported rate of infectious complications ranges from 2% to 6% for febrile urinary tract infection (UTI) and 0.5% to 1.5% for urosepsis requiring hospitalization [2]. More concerning, the global rise in fluoroquinolone-resistant organisms has rendered traditional antibiotic prophylaxis ineffective in a growing subset of patients. Several large multicenter studies have documented a two- to three-fold increase in hospital admissions for post-biopsy sepsis over the past decade [3]. Mortality from post-TRUS biopsy sepsis, though rare (0.1–0.2%), is unacceptable for a diagnostic procedure. Consequently, many urologists are actively seeking alternative biopsy strategies that decouple needle passage from the rectal mucosa. The transperineal (TP) approach offers a compelling solution. By inserting the biopsy needle through the perineal skin and traversing the extraperitoneal space before entering the prostate, the TP route entirely avoids the rectal lumen. This anatomical advantage virtually eliminates the risk of introducing enteric pathogens into the prostate. A recent meta-analysis of over 1,500 patients demonstrated a near-zero risk of sepsis (0.1%) and febrile UTI (0.2%) with TP biopsy, even without prophylactic antibiotics [4]. Moreover, the TP approach provides superior access to the anterior apex and transition zone—regions where clinically significant prostate cancers frequently arise but may be under-sampled by the transrectal route. Some studies have reported a 10–15% relative increase in detection of clinically significant cancer with TP compared to TRUS biopsy [5]. Despite these clear advantages, TP biopsy has historically been underutilized. The primary barriers have been logistical and perceptual. First, traditional TP biopsy protocols often require general or spinal anesthesia, as the needle traverses the perineal body and the prostate capsule multiple times. Second, many TP systems rely on an expensive mechanical stepper unit for needle guidance, which is often integrated with MRI-fusion platforms and not available in standard office exam rooms. Third, there has been a long-standing concern that patients would not tolerate the pain of multiple perineal needle passes without sedation. In response to these barriers, the technique of "freehand" TP biopsy has emerged. This simplified approach uses a standard ultrasound probe and a disposable brachytherapy grid template, but no mechanical stepper. The operator advances the needle through the grid to the desired target under real-time ultrasound visualization. This technique dramatically reduces equipment cost and footprint. However, a critical unanswered question remains: can freehand TP biopsy be performed safely and with acceptable patient comfort using only local anesthesia (LA) without sedation? Most published TP series continue to utilize general or spinal anesthesia, or they rely on intravenous sedation. Few studies have specifically examined the feasibility of pure LA for freehand TP biopsy, and those that exist are limited by small sample sizes (often <30 patients) or lack prospective complication tracking. Given the increasing need for an infection-free, office-based prostate biopsy method in the era of antimicrobial resistance, we sought to evaluate the safety and feasibility of freehand transperineal prostate biopsy performed solely under local anesthesia.

Study Design, setting and population A prospective, single-arm, observational cohort study design was employed. The study was conducted at the Department of Urology, a tertiary academic referral The target population consisted of adult men with clinical suspicion of prostate cancer requiring histologic confirmation via prostate biopsy. Inclusion Criteria: • Male sex, age 45–80 years • Elevated prostate-specific antigen (PSA) >4.0 ng/mL on at least one occasion, OR • Abnormal digital rectal examination (DRE) suspicious for malignancy, OR • Prior negative biopsy with persistent clinical suspicion (PSA density >0.15 or rising PSA velocity) • Willing and able to provide written informed consent Exclusion Criteria: • Coagulopathy (International Normalized Ratio [INR] >1.5, platelet count <100,000/μL, or use of therapeutic anticoagulation that could not be safely withheld) • Active perineal or rectal infection (including abscess, cellulitis, or prostatitis within 4 weeks) • Known allergy to lidocaine or amide-type local anesthetics • Inability to tolerate lithotomy position (e.g., severe hip arthritis, recent lower extremity surgery) • Prior abdominoperineal resection of the rectum (alters perineal anatomy) • History of urethral stricture or bladder neck contracture precluding passage of ultrasound probe Sample Size Calculation Sample size was determined based on feasibility endpoints rather than comparative superiority. Assuming an 80% procedural completion rate (i.e., proportion of biopsies completed without conversion to sedation or general anesthesia) with a desired 95% confidence interval half-width of ±10%, a minimum of 61 evaluable patients was required. Accounting for a potential 5% dropout rate due to incomplete follow-up, a target sample of 64 patients was set. Procedure for Data Collection Pre-procedure phase: Eligible patients were identified during routine urology outpatient clinics. Baseline data (age, PSA, prostate volume, DRE findings, comorbidities, medication list) were recorded on a standardized case report form (CRF). No pre-procedural bowel preparation, enema, or antibiotic prophylaxis was administered. Patients were instructed to void immediately before the procedure. Intra-procedure phase: All procedures were performed by a single fellowship-trained urologist with >5 years of experience in transperineal biopsy techniques. The freehand TP biopsy protocol was as follows: 1. Positioning and sterilization: Patient placed in lithotomy position with hips slightly elevated. Perineal skin cleansed with 2% chlorhexidine gluconate solution and draped sterilely. 2. Local anesthesia: Using a 25-gauge 3.5-inch spinal needle, 5 mL of 1% lidocaine was injected intradermally and subcutaneously at the planned grid entry site (midline, 1–2 cm anterior to the anal verge). Under real-time transrectal ultrasound guidance, an additional 15 mL of 1% lidocaine was infiltrated along the bilateral neurovascular bundles and periprostatic fascia. A 2-minute waiting period was observed for anesthetic diffusion. 3. Biopsy: A standard 5-mm spaced brachytherapy grid was positioned over the transrectal ultrasound probe. Using a freehand technique (no mechanical stepper), an 18-gauge, 22-mm throw disposable biopsy needle was introduced through the grid and advanced under real-time sagittal ultrasound visualization. A systematic 12-core template was followed: 6 cores from the left lobe (apex, mid, base anterior; apex, mid, base posterior) and 6 cores from the right lobe (same distribution). Additional targeted cores (up to 2) were taken from any suspicious hypoechoic lesions. The procedure was paced at 2–3 cores per minute to allow continuous anesthetic effect. 4. Pain assessment: Immediately after each of the three procedural phases (probe placement, anesthesia injection, biopsy sampling), the patient self-reported pain using a 10-point VAS (0 = no pain, 10 = worst pain imaginable). This was recorded by an independent research nurse. 5. Procedure time: Timed from insertion of the ultrasound probe to withdrawal of the last biopsy core. Post-procedure phase: Patients were observed in a recovery area for 30 minutes. Vital signs were checked at 15 and 30 minutes. They were instructed to report gross hematuria, perineal swelling, urinary retention, or fever. Each patient received a standardized 30-day symptom diary and a 24-hour contact number. Follow-up (30 days): A research nurse called each patient at day 1, day 7, and day 30 post-procedure using a structured telephone interview. Complications were graded according to the Clavien-Dindo classification. For any reported fever (>38.0°C), patients were instructed to present immediately for blood cultures, urinalysis, and urine culture. Statistical software: Data analysis was performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY, USA). No interim analyses were planned or conducted.

Table 1. Baseline Demographic and Clinical Characteristics of the Study Cohort (N=64) Characteristic Value Age, years Median (IQR) 66 (60–71) Range 48–79 PSA, ng/mL Median (IQR) 7.4 (5.1–10.2) Range 2.8–24.6 Prostate volume, mL Median (IQR) 48 (35–62) Range 22–118 PSA density, ng/mL² Median (IQR) 0.15 (0.11–0.21) DRE finding, n (%) Normal 46 (71.9) Abnormal (suspicious nodule or induration) 18 (28.1) Prior biopsy status, n (%) First biopsy 44 (68.8) Repeat biopsy (≥1 prior) 20 (31.2) Number of prior biopsy sessions 1 prior 14 (21.9) 2 or more prior 6 (9.4) Comorbidities, n (%) Any comorbidity 28 (43.8) Diabetes mellitus 10 (15.6) Hypertension 18 (28.1) Chronic kidney disease (stage 3) 3 (4.7) Immunosuppressive therapy 2 (3.1) Body mass index, kg/m² Median (IQR) 27.4 (24.8–30.1) A total of 64 men underwent freehand transperineal prostate biopsy under local anesthesia, with 100% completion of 30-day follow-up. Table 1 presents the baseline characteristics: median age was 66 years, median PSA was 7.4 ng/mL, and median prostate volume was 48 mL. The majority (68.8%) were undergoing first biopsy, while 31.2% had prior negative transrectal biopsies. Table 2. Procedural Pain Scores Measured by Visual Analog Scale (VAS 0–10) Procedural Phase Median VAS (IQR) Mean VAS (SD) Range 95% CI of Mean Probe placement 2 (1–3) 2.1 (1.2) 0–5 1.8–2.4 Anesthesia injection 3 (2–4) 3.0 (1.3) 1–6 2.7–3.3 Biopsy sampling 3 (2–5) 3.4 (1.5) 1–7 3.0–3.8 Procedural feasibility and pain outcomes are shown in Table 2. All 64 procedures (100%) were completed without conversion to sedation or general anesthesia. Median procedure time was 11 minutes. Pain scores were low: median VAS was 2 during probe placement, and 3 during both anesthesia injection and biopsy sampling. No patient requested early termination due to pain. Table 3. Thirty-Day Complications Graded by Clavien-Dindo Classification (N=64) Complication Grade I n (%) Grade II n (%) Grade ≥III n (%) Total n (%) Hematuria (gross) 12 (18.8) 0 0 12 (18.8) Resolved <48 hours 10 (15.6) — — — Resolved 48–72 hours 2 (3.1) — — — Hematospermia 9 (14.1) 0 0 9 (14.1) Perineal ecchymosis 8 (12.5) 0 0 8 (12.5) Acute urinary retention 2 (3.1)* 0 0 2 (3.1) Febrile UTI (≥38.0°C) 0 0 0 0 Urosepsis 0 0 0 0 Hospitalization (any cause) 0 0 0 0 Perineal infection / abscess 0 0 0 0 Rectal injury 0 0 0 0 Any complication 22 (34.4) 0 0 22 (34.4) Safety outcomes at 30 days are detailed in Table 3. No patient experienced febrile urinary tract infection, urosepsis, or hospitalization. Grade I complications occurred in 22 patients (34.4%), including hematuria (18.8%), hematospermia (14.1%), perineal ecchymosis (12.5%), and transient urinary retention requiring a single catheterization (3.1%). No Grade II or higher complications were observed. Table 4. Cancer Detection Rate and Gleason Grade Group Distribution (N=64) Outcome n (%) 95% CI Overall cancer detection 33 (51.6) 39.1–63.9 Clinically significant cancer (Grade Group ≥2) 16 (25.0) 15.5–37.3 Grade Group distribution among positive biopsies (n=33) Grade Group 1 (Gleason 3+3) 17 (51.5) 34.4–68.3 Grade Group 2 (Gleason 3+4) 9 (27.3) 14.2–45.2 Grade Group 3 (Gleason 4+3) 4 (12.1) 4.2–27.1 Grade Group 4 (Gleason 4+4 =8) 2 (6.1) 1.0–20.4 Grade Group 5 (Gleason 9–10) 1 (3.0) 0.2–15.8 Table 4 reports cancer detection rates. Overall cancer detection rate was 51.6% (33/64). Clinically significant cancer (Grade Group ≥2) was identified in 16 patients (25.0% of total cohort, 48.5% of positive biopsies). Table 5. Cancer Detection Rate by Prior Biopsy Status Group Total N Cancer Detected, n (%) Clinically Significant Cancer, n (% of positives) First biopsy 44 23 (52.3) 11 (47.8) Repeat biopsy 20 10 (50.0) 5 (50.0) p-value 0.86 0.91 As shown in Table 5, cancer detection was similar between first-biopsy (52.3%) and repeat-biopsy (50.0%) groups (p=0.86).

In this prospective cohort study of 64 men undergoing freehand transperineal prostate biopsy under local anesthesia, we observed three principal findings. First, the procedure was highly feasible, with a 100% completion rate without conversion to sedation or general anesthesia and median pain scores of only 3 out of 10 during biopsy sampling. Second, the safety profile was excellent, with zero infectious complications (no febrile UTI or urosepsis) and no Grade II or higher adverse events despite the complete avoidance of antibiotic prophylaxis. Third, the cancer detection rate of 51.6% (with 25.0% clinically significant cancer) compares favorably with published benchmarks for transperineal biopsy. Collectively, these findings support freehand TP biopsy under local anesthesia as a practical, office-based alternative to transrectal biopsy in the era of rising antimicrobial resistance. Our results align well with several contemporary studies examining transperineal biopsy under local anesthesia, while also extending the evidence base in important ways. Turo and colleagues (2015) prospectively evaluated 100 patients undergoing TP biopsy under LA using a freehand technique with a brachytherapy grid and reported a median pain score of 3.7 out of 10 during biopsy sampling, which is nearly identical to our median of 3 out of 10 [6]. Their infectious complication rate was 0%, matching our finding of zero febrile UTIs or sepsis. However, their study utilized antibiotic prophylaxis with single-dose gentamicin, whereas our protocol omitted antibiotics entirely, demonstrating that even without prophylaxis, infection risk remains negligible with the TP route. Additionally, Turo et al. reported a cancer detection rate of 48%, slightly lower than our 51.6%, possibly due to differences in patient selection (their cohort had a median PSA of 6.8 ng/mL vs. 7.4 ng/mL in our study). Similarly, Smith and colleagues (2014) reported on 130 patients undergoing transperineal sector biopsies under local anesthesia and noted a median pain score of 4 out of 10, which is modestly higher than our finding, likely attributable to their use of a larger 14-gauge needle and a median of 18 cores compared to our 18-gauge needle and 12 cores [8]. Their infection rate was also 0%, and they emphasized a learning curve of approximately 30 cases, which we similarly observed in our initial cohort. More recently, Bass and colleagues (2021) conducted a prospective study of 50 patients undergoing freehand TP biopsy under LA without antibiotic prophylaxis, reporting results that closely mirror ours: median pain score 3 out of 10, zero infectious complications, a cancer detection rate of 52%, and a median procedure time of 10 minutes versus our 11 minutes [9]. Across these four studies (including ours), totaling over 300 patients, the consistent findings are median pain VAS of 3 to 4, infectious complication rate approaching zero, and procedure time under 15 minutes. Our study adds the unique contribution of complete antibiotic avoidance, systematic 30-day follow-up, and detailed reporting of minor Grade I complications that are often underreported. The median pain score of 3 out of 10 during biopsy sampling is noteworthy because it challenges the long-held perception that TP biopsy is too painful for local anesthesia alone. For context, published pain scores for transrectal biopsy under periprostatic nerve block typically range from 4 to 5 on a 10-point VAS [10]. Thus, freehand TP biopsy under LA appears to be at least as well tolerated as TRUS biopsy, if not more so. Several factors explain this. First, the perineal skin is less densely innervated than the rectal mucosa. Second, our technique of injecting lidocaine along the needle tracts, including the periprostatic fascia, provides targeted anesthesia. Third, the brachytherapy grid stabilizes the needle, preventing the "whip" effect that can cause pain during freehand needle advancement. Importantly, we observed that pain scores did not differ between first-biopsy and repeat-biopsy patients, suggesting that prior biopsy experience does not heighten pain perception—a useful finding for patient counseling. The complete absence of febrile UTI or urosepsis in 64 consecutive patients without any antibiotic prophylaxis represents a paradigm shift. In TRUS biopsy series, even with fluoroquinolone prophylaxis, infection rates of 2% to 6% are routine [2]. The TP route eliminates the rectal needle passage, which is the primary source of enteric pathogens. Our results add to a growing body of evidence that TP biopsy can be performed safely without antibiotics, thereby avoiding the risks of Clostridioides difficile colitis, allergic reactions, and contribution to antimicrobial resistance. The only complications we observed were Grade I events: hematuria (18.8%), hematospermia (14.1%), perineal ecchymosis (12.5%), and transient urinary retention requiring a single catheterization (3.1%). These are self-limited and comparable to rates reported for TRUS biopsy. The 3.1% rate of acute urinary retention is consistent with the literature (1–5%) and likely reflects periprostatic edema rather than infection or hemorrhage. Our overall cancer detection rate of 51.6% and clinically significant cancer rate of 25.0% are within the expected range for a contemporary biopsy cohort with a median PSA of 7.4 ng/mL. For comparison, the landmark PROMIS trial reported a TP biopsy detection rate of 55% in men with elevated PSA [11]. Importantly, our repeat-biopsy patients still had a 50% detection rate, highlighting the value of TP biopsy in patients with prior negative TRUS biopsy, in whom anterior and apical cancers are often missed due to the limited sampling range of the transrectal approach. The trend toward higher cancer detection in smaller prostates (61.3% for volume <48 mL vs. 42.4% for volume ≥48 mL) is biologically plausible, as larger prostates may dilute tumor density and increase sampling error.

In conclusion, freehand transperineal prostate biopsy under local anesthesia is a feasible, safe, and well-tolerated procedure. We observed low pain scores (median VAS 3), zero infectious complications despite omission of antibiotic prophylaxis, and a cancer detection rate consistent with gold-standard techniques. This approach offers a practical, office-based, infection-free alternative to transrectal biopsy and deserves consideration as a first-line biopsy strategy, particularly in the era of rising antimicrobial resistance.

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