Patient-reported pain associated with grid-based transperineal magnetic resonance imaging (MRI)/ultrasound (US) software fusion biopsy of the prostate under local anesthesia: a multicenter experience

Introduction

The transperineal (TP) approach for biopsy of the prostate is becoming gold standard in clinical practice, as advocated by the contemporary guidelines (1). Firstly, while recent evidence demonstrates no significant difference (2), TP biopsy may be superior to transrectal (TR) biopsy in diagnostic performance when combined with magnetic resonance imaging (MRI)/ultrasound (US) fusion (3-6), likely associated with improved cancer detection rates for anterior tumors (7). Secondly, the TP approach typically does not involve violation of the rectal mucosa, hence this route of bacterial spread is avoided, the risk of urinary tract infection (UTI) or sepsis is significantly decreased if not virtually eliminated with a TP biopsy, compared to a TR procedure (8,9). However, a TP biopsy requires the needle to penetrate through highly innervated layers of the pelvic floor. This approach, as opposed to the TR biopsy, has been traditionally linked to an increased risk of significant pain or discomfort to the patient, necessitating the use of higher-grade anesthesia (10). However, office-based TP biopsy under local anesthesia (LA) is becoming increasingly popular and several reports demonstrating safety with this setting have been recently published in the literature (11-15). On the other hand, some early studies concluded that TP biopsy under LA may be significantly more painful than a TR biopsy under LA (16-18). More recent studies have shown comparable pain scores (19-21) and a large multicenter, randomized trial aimed to provide high-quality evidence has been developed (22). Also, given that some patients may still require conversion to sedation during TP under LA (12), the knowledge gap in regard to which patients would be more likely to experience higher degree of pain during the procedure, appears to be clinically significant.

In this retrospective observational study, we aimed to investigate the degree of patient-reported pain associated with MRI/US TP fusion biopsy of the prostate being performed under LA, as well as to study for possible factors associated with increased risk of significant pain (SP) with this setting. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-23-139/rc).

Methods

We retrospectively analyzed consecutive patients without a prior diagnosis of prostate cancer (PC) who underwent MRI/US software fusion biopsy of the prostate under LA at two centers (European Health Center Otwock, affiliated with the Second Department of Urology at Centre of Postgraduate Medical Education, Warsaw, and Department of Urology at St. Anna Hospital, Piaseczno), between May 2020 and April 2022. Data were collected in May 2022 from medical patient records and included: age, previous medical history, pre-biopsy prostate-specific antigen (PSA) level, MRI report, biopsy procedure report, and pathology report. Only patients with positive MRI (i.e., PIRADS category 3 or higher) were included. Patients for whom procedure-associated pain reports were not available were excluded from the study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). According to local law regulations, due to the retrospective and noninterventional character of the study, there was no need for ethics approval nor patient informed consent.

MRI/US fusion biopsy

All biopsies were performed with TP approach, using the KOELIS Trinity MRI/US OBT Fusion^® system, with the aid of the KOELIS Mini Grid™ device. Two experienced urologists performed all the procedures at the two participating centers. A digital rectal examination (DRE) was carried out and recorded just before the procedure. Every biopsy included cores targeted at all the PIRADS ≥3 lesions identified in the MRI report. Occasionally, additional lesions considered suspicious by the performing urologists might have been subject to targeted biopsy. The minimal number of targeted cores was 3 per lesion in every case and additional cores might have been taken in case of larger or more complex lesions. Systematic biopsy was a part of the procedure in every biopsy-naïve patient. In other patients, systematic biopsy was performed if deemed necessary by the urologist, based on individual risk assessment. No specific template for systematic biopsy was used. The number and distribution of systematic cores were at the discretion of the performing urologist, dependent predominantly on the lesion location and size, as well as prostate volume (PV). Cores were taken with an 18-gauge needle. Most of the patients received preprocedural antibiotic prophylaxis consisting of a single dose of either 400 mg cefixime or 960 trimethoprim/sulfamethoxazole, administered 2 hours prior to the biopsy.

Local anesthesia procedure

Patients did not receive pre-emptive analgesia nor sedation. In every case, after placing and draping the patient in the lithotomy position, and skin decontamination, firstly, a total of 10 mL of 1% lidocaine solution was subcutaneously injected with a fine needle at multiple sites to the perineal area. Secondly, after inserting the TR probe into the rectum and visualization of the prostate, a TP bilateral injection of 0.5% lidocaine was administered with a 22-gauge needle to the presumed localization of neurovascular bundles along the posterolateral periprostatic area, with 15–20 mL of solution being injected on each side (larger amounts with larger PV). The total lidocaine dose was 175–200 mg and never exceeded the World Health Organization recommended maximum dose of 4.5 mg/kg or 300 mg. No additional intravenous sedation was administered.

Pain reporting

Immediately after the procedure patients were asked to report their overall experience with the biopsy on the Wong-Baker FACES Pain Rating Scale diagram (available at https://wongbakerfaces.org), shown by the performing urologist. The original version of the diagram, consisting of 0-1-2-3-4-5 numbers, was used in the office. For the purpose of this study, we converted (doubled) all the patient reported scores to the updated scale of 0-2-4-6-8-10. We defined SP as reported pain score of ≥6, which corresponds to the three most upset faces.

Other definitions

Clinically significant prostate cancer (csPC) was defined as grade group ≥2 cancer detected at biopsy.

Statistical analysis

Categorical and quantitative variables were reported as numbers (with percentages) and medians (with interquartile ranges), respectively. Percentages and continuous variables were compared with Chi-square and Mann-Whitney test, respectively. Associations between categorical and continuous variables and a dependent variable were investigated using logistic regression models. Outcomes of analyses were expressed as odds ratios (OR) with 95% confidence intervals (95% CIs). We considered the results statistically significant if P value <0.05. Additionally, to assess the level of discrimination we performed receiver operating characteristics (ROC) analysis and calculated area under the curve (AUC). Optimal threshold for discrimination was calculated using the Youden’s method. Statistical analyses were performed using SPSS (IBM, version 24.0.0.0) and Matlab (MathWorks, version R2023a).

Results

We identified 459 patients who met the inclusion criteria. After exclusion of patients for whom pain reports were not available (n=160), 299 patients were eventually included into the analyses. The patient characteristics are presented in Table 1.

The median score of patient-reported pain was 2 (IQR: 2–4). Distribution of pain scores is presented in Figure 1. Significant pain (score ≥6) was reported by 55 (18.4%) patients.

Figure 1 Distribution of patient-reported degree of pain scores.

Comparison of patient characteristics in regard to the level of reported pain (significant versus non-significant) is provided in Table 2. Associations between patient-related factors and significant pain, computed with univariable models, are presented in Table 3. As only one factor demonstrated significant association with the dependent variable, we did not proceed with multivariable modeling.

For patient age we computed an ROC model measuring the level of discrimination of SP from non-SP and revealed the AUC to be 0.65 (95% CI: 0.58–0.72). The optimal threshold for discrimination was identified as age of less than 62 years, with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) being 55%, 72%, 30%, and 88%, respectively. Comparison of SP rates between patients aged <62 and ≥62 years revealed that age of ≥62 years was significantly negatively associated with SP (OR =0.33, 95% CI: 0.18–0.60, P<0.001), with SP being reported by 12.5% of patients aged ≥62 years, versus 30.3% in patients <62 years of age.

The median number of cores taken was 10 (IQR: 9–12). Interestingly, on a univariable model, increasing number of cores was negatively associated with SP (OR =0.86, 95% CI: 0.75–0.97, P=0.016). Patient age was not significantly associated with the number of cores taken being equal to or greater than median, i.e., ≥10 (OR =1.01, 95% CI: 0.97–1.05, P=0.73).

Any PC and csPC were diagnosed in 196 (65.6%) and 122 (40.8%) patients, respectively. Men who reported SP tended to be diagnosed with csPC less often than non-SP patients [17/55 (30.9%) vs. 105/244 (43.0%), P=0.10]. Rates for any PC were similar between the two groups [34/55 (61.8%) vs. 162/244 (66.4%), P=0.52].

Discussion

We present results of a study aimed to investigate the risk of significant pain in patients undergoing TP biopsy of the prostate under LA. We demonstrate that the procedure, if performed under LA, is generally well tolerated in terms of pain, with 18% of the patients having reported their pain as either 6, 8, or 10 on a 0–10 score, i.e., at the level at which we considered the pain to be significant.

In general, the results of our study are in line with multiple other papers already published in the literature, as TP biopsy of the prostate has already been reported to be well tolerated by patients. Moreover, marked heterogeneity in regard to the LA technique used in particular studies, selective use of pre-emptive oral sedation in some studies, as well as LA procedure not being routinely described in detail, impair consideration of our results on the background of available evidence. Nevertheless, in most studies in which a 0–10 pain scale (Visual Analogue Scale or Numerical Rating Scale) was employed, neither mean nor median patient reported overall pain exceeded 4 out of 10 (11,13,15,17,18,23,24), reflecting good efficacy of LA. In one small cohort, mean patient-reported pain with TP approach was 8.02 (out of 10) (16), which, however, may be considered a significantly outlying result. Interestingly, the recently published results of the APROPOS study demonstrate that anesthesia using perineal nerve block, instead of periprostatic block, may lead to improved pain control and patient satisfaction (25).

While the abovementioned studies, as well as our study, evaluated the patient-reported pain in general, some researchers aimed to assess the level of pain separately for particular stages of the procedure, demonstrating that the highest degree of discomfort was associated with the administration of LA, becoming lower at the time of biopsy gun fire (2,12,14,26,27). However, we believe that the overall patient feedback may be considered a reflection of their general satisfaction with the anesthesia type. An interesting outcome was proposed by Hong et al., who reported that the vast majority of patients (85%) would opt for a repeat TP biopsy under LA if the need for the procedure arises again (14). In the study by Kum et al., 9% of patients required sedation in addition to LA (12), which may serve as another outcome for analyzing patient tolerability of TP biopsy under LA. As including and measuring the abovementioned alternative outcomes could have led to even better evaluation of patient experience with TP biopsy under LA, lack of this data may be considered a minor limitation to our study. Moreover, pain associated with prostate biopsy may not be the only aspect of discomfort perceived by the patient. Embarrassment, as well as other inconveniences related to unnatural patient positioning or rectal manipulation may serve as other components of procedure tolerability. Whether this influenced the degree of reported pain, remains subject to speculations. Considering this widened scope of tolerability for the purpose of future study design is necessary.

As our results confirm the good pain tolerability of TP biopsy performed under LA, they may serve as aid in developing strategies aimed at improving cost-effectiveness of PC diagnostic process. A large-cohort analysis demonstrated that even with intravenous anesthesia the mean overall cost of a procedure, which included both biopsy and re-presentations, was significantly lower for TP than TR (28). One could suppose that replacing higher-grade anesthesia with LA could have further increased the difference in favor of TP. Recently, Hogan et al. reported that TP biopsy under LA consumed significantly less resources than TP performed under general anesthesia (26). Further studies aimed to verify the hypothesis of TP biopsy under LA being the most cost-effective approach are necessary.

In our study, we also investigated the associations between possible patient-related factors and the risk of pain during TP MRI/US fusion biopsy of the prostate. Among other variables included into our analyzes, only patient age demonstrated significant association with SP, with older patient demonstrating better tolerance of the procedure. This finding is in line with a previously published study by Marra et al. (27), who also reported age to be a protective factor for severe biopsy pain. The role of aging in increasing the pain tolerance threshold is well-established in the literature, although the exact nature of the process still remains unclear (29,30). Although the ROC AUC for patient age discriminating between SP and non-SP fell slightly below the universally used level of acceptance (i.e., 0.70), given the significant associations demonstrated in other analyses, we believe that our results may be helpful in preprocedural counselling in patients especially concerned about the risk of pain or discomfort. While further studies would be necessary to establish the role of higher-grade anesthesia in patients at predefined, increased risk of SP during TP biopsy under LA, one could consider our results significant enough to discuss pre-emptive analgesia or mild sedation, or even general anesthesia, with younger men or patients who report low thresholds of pain tolerance, as well as to reassure patients deemed to be at lower risk of significant pain.

Although we assumed that patients who had been already familiar with the procedure would have experienced lower levels of discomfort, our data show that being biopsy-naïve was not associated with SP. As local concentration of the anesthetic agent injected into the periprostatic area might have been smaller with larger prostates, we investigated for a link between PV and SP, however, finding no significant association. We hypothesized that the location of lesion and thus targeting a number of cores at different sites in the prostate could have influenced the degree of pain. As the anterior fibrous stroma (AFS) differs from the other prostate zones in regard to its histology, being relatively less vascular and more fibrous (31), we decided to evaluate lesion being located in the AFS as a possible factor for lower risk of SP. Despite, indeed, slightly lower rates of SP with AFS being targeted during the procedure, the association was non-significant. A possible explanation is that it might have been not the biopsy needle shots itself, but the LA injection that was responsible for most of the pain experienced by the patients (2,12,14,26,27).

We hypothesized that in patients with an ongoing chronic inflammatory process in the prostate, a condition whose clinical image may rise suspicion of csPC and lead to an unnecessary biopsy (32), the periprocedural pain would be increased, as prostatitis or chronic pelvic pain syndrome (CPPS) is commonly linked to altered nociception in the pelvis (33). As DRE status and PSA level, as well as PSAD, might have been different in those patients, as compared to patients truly harboring PC, we investigated those factors for a possible link with SP, although, no association was found. Also, any differences in cancer detection rates (any PC or csPC) between SP and non-SP patients were non-significant, which is in line with already published evidence (27). Unfortunately, we lack data on the presence of pathologic features of prostatitis in our patients, as our institutional pathologist do not typically mention this fact in the biopsy pathology report in case of PC being diagnosed in the specimen. Nevertheless, even if such an association existed, we would not consider it clinically significant, as the pathology status is not known before biopsy and thus cannot not be used for pre-procedural decision making in regard to the anesthesia type. However, reliable history in regard to prostatitis or CPPS could have been included as a possible factor for SP in our analyses and lack of this data may be considered a limitation to our study.

The association between higher number of cores taken and lower rates of SP is difficult to discuss, as many would expect the relation to be opposite. A possible explanation for this finding would be that the performing urologist could have decided to take less systematic cores during a procedure in which a patient was demonstrating worse tolerance, which could have caused a bias. However, due to the retrospective design of our study, the exact explanation of this problem remains a matter of speculation. In our opinion, this topic is worth further, prospective investigation, as if an association between pain and biopsy quality exists (e.g., because of less cores being taken or targets being missed due to patient moving on the table), this would have important clinical implications. However, Hogan et al. (26) did not find a difference in cancer detection rates between TP biopsies under local or general anesthesia.

Our definition of SP representing a score of ≥6 was arbitrary. As the scale used for pain reporting was six-degree, we considered the “worse” half of the scale (scores 6–10) as “more pain”, i.e., SP, as compared to “less (or no) pain” with scores 0–4 (the “better” half of the scale). Moreover, only the faces corresponding to scores 6–10 depict unequivocally negative feelings. Whether those scores were in fact considered “significant” by the patients, remains a matter of speculations. Importantly, the patients might have also expressed the significance of pain by a decrease in ability to cooperate, possibly reflected in, e.g., prolonged duration of the procedure, increased risk of biopsy needle missing the target, or bleeding complications. While our results do not provide answers to this hypothesis, we consider it an interesting area for future research. Differentiation between procedure stages for the purpose of pain reporting could further help in gaining deeper understanding of this aspect.

Our study was performed in two separate institutions, with the same method of assessing patient-reported pain being used. We consider it a strength, especially given the fact, that the comparison of patient characteristics demonstrated the patient profile to be markedly different between the two centers, making our results more representative of general, heterogeneous population.

In addition to the issues already mentioned in the above paragraphs, the retrospective character of the study remains its major limitation. Being better aware of possible risk factors of decreased pain threshold within the pelvis, as well as taking into consideration various outcomes helpful in measuring patient satisfaction with anesthesia, may represent other issues crucial for designing further prospective studies. We believe that such studies are necessary before any strong recommendations in regard to details of periprocedural anesthesia in patients undergoing TP biopsy can be made.

Conclusions

We present a multicenter study demonstrating that grid-based TP MRI/US software fusion prostate biopsy under LA is associated with low levels of patient-reported pain. Given that the TP approach is being advocated as gold standard for prostate biopsy, our evidence may further help in wide adoption of the procedure being performed under LA in ambulatory practice. We also demonstrated that older age was inversely associated with the risk of reporting significant pain, which may justify discussing pre-emptive analgesia or higher-grade anesthesia in younger patients, especially if low threshold of pain tolerance is reported. Further research is necessary to prospectively confirm our findings.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-23-139/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-139/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-139/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-139/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspect of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). According to local law regulations, due to the retrospective and noninterventional character of the study, there was no need for ethics approval nor patient informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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