Tolerability of Transperineal Prostate Biopsy Under Local Anaesthetic Using Pre-Emptive Over-the-Counter Analgesia: An Interventional Study in Patients with Abnormal Clinical Prostate Findings

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review:  Tolerability of transperineal prostate biopsy under local anaesthetic using pre-emptive over-the-counter analgesia: an interventional study in patients with abnormal clinical prostate findings at the Sydney Adventist Hospital

The paper explores a compelling clinical inquiry, specifically investigating the impact of administering analgesics before a Transperineal prostate biopsy. The study focuses on whether taking 1g of paracetamol and 400mg of ibuprofen one hour before the biopsy reduces pain levels during key stages of the procedure (1. Probe insertion, 2. Applying local anesthesia, 3. Taking biopsies).The study's findings provide valuable insights into the relevance of Non-Steroidal Anti-Inflammatory Drugs in this context. The authors demonstrate no significant changes and conclude that Transperineal biopsy can be feasibly conducted under local anesthesia with low pain levels, even without additional oral pain medication.

The paper exhibits clear writing, and the conclusions are commendable. Nonetheless, certain aspects require further clarification. Specifically:

1.    Introduction: Transperineal prostate biopsy is the key diagnostic tool for evaluating prostate cancer and may be feasible under local anaesthetic (LA)

è I recommand refrasing in is feasible under local anaesthetic

2.    Methods: Why was the quantity of local anesthesia not standardized in administration? What were the reasons for varying the volume in either direction? How was the distribution managed? Please give a detailed description of the volume used per patient in each group etc.

3.    Methods: Why, despite the prospective study design, were there inconsistent group sizes included in the two arms? Were there challenges with recruitment, and if so, what were the reasons behind them?

4.    Why were patients who could not tolerate a biopsy under local anesthesia excluded? It would have been intriguing to explore whether oral NSAIDs could reduce the discontinuation rate. These results could be included in the supplementary section for further examination.

5.    It is mentioned that 4 target biopsies were taken; however, it is not reported how many systematic biopsies were obtained. The total number of cores should be separately documented for each group to provide a comprehensive comparison.

6.    Results: The localization of the targets and its impact on pain remains of interest to the readers, as in transrectal procedures, this has sometimes yielded variations in studies.

7.    In the results, there is a lack of precise information regarding the quantities of local anesthesia. The correlations with the overall amount of administered lidocaine are mentioned, but specific values for each group should be provided. It is essential to delineate the exact amounts of applied local anesthesia for each group. Additionally, it would be pertinent to elucidate whether there was a threshold dosage under which all patients remained below 3 on VAS.

8.    Results: Furthermore, the readership would find the relationship between prostate size and the amount of local anesthetic intriguing.

9.    Discussion: In the discussion, this passage is referenced:

Similarly, a non-systematic literature review on analgesia forms for TP biopsy observed higher volumes of LA were linked with lower VAS-Overall scores, but with higher VAS-LA infiltration scores.[25] This corroborates with the evidence above that LA infiltration is the most painful part of the procedure and suggests increased volume of LA at this point of the procedure may improve its overall tolerability.

However, in the results section, it is demonstrated that:

There were various negative correlations found to be statistically significant. In the intervention group, the observed negative correlations were: VAS-Overall and volume of LA; VAS-Probe insertion and prostate size; and VAS-LA infiltration and volume of LA. In the control group, there was one observed negative correlation between VAS-LA infiltration and age.

I find these statements contradictory and believe that the volume of local anesthetic administration should be discussed in more detail in relation to the temporary increase in pain versus the subsequent pain relief. 

In considering the entirety of this manuscript, it becomes evident that significant revisions are warranted.

Author Response

Introduction

• Reviewer 1: Rephrasing the introduction from “Transperineal prostate biopsy is the key diagnostic tool for evaluating prostate cancer and may be feasible under local anaesthetic (LA)” to “is feasible under local anaesthetic.”
  • Thank you for this comment, this has now been done.

Method

• Reviewer 1: Why was the quantity of local anesthetic not standardized in administration? What were the reasons for varying the volume in either direction? How was the distribution managed? Please give a detailed description of the volume used per patient in each group etc.
  • Thank you for this comment. The absence of a standardized LA volume is a limitation in this study. The dose of LA used was based on an experienced surgeon’s clinical expertise to achieve appropriate analgesia during TP biopsy. The surgeon performing the biopsies is highly experienced with this procedure and accounted for factors including patient size and biopsy target when achieving appropriate analgesia. While there was no standardized dose of LA given, the amount of LA required to achieve analgesia was measured per patient and we have now amended table 1 to reflect the average and median LA used per group.

• Reviewer 1: Why, despite the prospective study design, were there inconsistent group sizes included in the two arms? Were there challenges with recruitment, and if so, what were the reasons behind them?
  • Thank you for this comment. There were inconsistent group sizes included in the two arms not because there were challenges with recruitment, but because of time restraints. This project began as a quality improvement audit which only collected data for the control arm. The prospective nature of the study is in reference to the intervention group for which data collection began a year after the control group.
• Reviewer 1: Why were patients who could not tolerate a biopsy under local anaesthesia excluded? It would have been intriguing to explore whether oral NSAIDs could reduce the discontinuation rate. These results could be included in the supplementary section for further examination.
  • Thank you for this comment. Three patients were excluded because they could not tolerate the TP biopsy under local anesthetic due to anxiety, anal spasm, and anastomosis (see Figure 2) as assessed by a surgeon experienced with this protocol. As such, no data was collected with these patients beyond that the procedure had to be stopped. Had these patients completed the survey, we agree it would be appropriate for their results to be included.
• Reviewer 1: It is mentioned that 4 target biopsies were taken; however, it is not reported how many systematic biopsies were obtained. The total number of cores should be separately documented for each group to provide a comprehensive comparison.
  • Thank you for this comment. There were no systemic biopsies obtained as all TP biopsies were targeted in this study. Some patients had samples from multiple sites. Four biopsies were taken at each site. We now included the mean and median total number of cores per group in table 1.
  • New table:

Results

• Reviewer 1: The localization of the targets and its impact on pain remains of interest to the readers, as in transrectal procedures, this has sometimes yielded variations in
  • Thank you for this comment.

• Reviewer 1: In the results, there is a lack of precise information regarding the quantities of local The correlations with the overall amount of administered lidocaine are mentioned, but specific values for each group should be provided. It is essential to delineate the exact amounts of applied local anesthesia for each group. Additionally, it would be pertinent to elucidate whether there was a threshold dosage under which all patients remained below 3 on VAS.
  • Thank you for this comment. We have now added the mean and median volume of LA used per group in table 1.
  • In addition, we have added an Appendix B to show the association between volume of LA and pain scores. In summary there was insufficient data to determine as to whether there is a threshold dose of local anesthetic associated with a VAS of under 3.
• Reviewer 1: Furthermore, the readership would find the relationship between prostate size and the amount of local anesthetic intriguing.
  • Thank you for this comment. We agree the relationship between prostate size and local anesthetic would be interesting. It is our view that rather than prostate size, the number of sites for targeted TP biopsies would affect the volume of local anesthetic used. This was outside the scope of our study which examined the effect of over the counter analgesia on pain with TP biopsies. Although we did not include this, we did analyse our data and found no relationship between prostate size and the amount of local anesthetic. This can be demonstrated in the following two graphs comparing the prostate size (cc) and the volume of local anaesthetic in the control and intervention group respectively.

Figure 1: Prostate size vs volume of LA (mL) in the control group

Figure 2: Prostate size vs volume of LA (mL) in the intervention group.

Discussion:

• Reviewer 1: Contradiction between results and discussion – I find these [following) statements contradictory and believe that the volume of local anesthetic administration should be discussed in more detail in relation to the temporary increase in pain versus the subsequent pain relief.
  • Discussion referenced: “Similarly, a non-systematic literature review on analgesia forms for TP biopsyobserved higher volumes of LA were linked with lower VAS-Overall scores, butwith higher VAS-LA infiltration scores.[25] This corroborates with the evidenceabove that LA infiltration is the most painful part of the procedure and suggestsincreased volume of LA at this point of the procedure may improve its overall”
  • Vs results referenced: “However, in the results section, it is demonstrated that:There were various negative correlations found to be statistically significant. Inthe intervention group, the observed negative correlations were: VAS-Overalland volume of LA; VAS-Probe insertion and prostate size; and VAS-LAinfiltration and volume of LA. In the control group, there was one observednegative correlation between VAS-LA infiltration and age.
  • Thank you for this comment. Our results are consistent with the discussion and literature in that the VAS at LA infiltration was the most painful part of the procedure in both our control and intervention group. Similarly, our results found negative correlations between VAS-overall and volume of LA which is also consistent with what is reported in the literature and referenced in our discussion.
  • However, it is true that reference 25 mentioned in the discussion found some evidence that higher volumes of LA were linked with higher VAS LA infiltration scores. In contrast, our results found that higher volumes of LA were linked with lower VAS LA infiltration (p=0.02). This is only seen within our intervention group and not control group and may suggest over the counter analgesia helps relieve the most painful part of the biopsy.
  • We have analyzed reference 25 in greater detail to better understand the discrepancy. The reference here is the 2017 paper, “Transperineal prostate biopsy - tips for analgesia” by McGrath S et al. In summary, there is no strong evidence indicating a higher volume of LA is linked with greater VAS scores at LA infiltration.
  • This is because McGrath et al’s nonsystematic literature review refers to three studies with each using a different type of block and standardized amount of LA.
  • As such, none of these papers measure a direct relationship between the volume of LA used and VAS at LA infiltration and multiple confounders between papers would preclude a clear relationship between pain scores at LA infiltration and the volume of LA used.
  • We have amended the manuscript to include these points.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Novel idea and results worth presenting. However, a few minor issues:

Study design: Patients who could not tolerate the procedure should not be excluded from the study since the goal of the study is to assess pain and tolerability. No standardization of dose of LA used. Figure 2 is misleading, this is not a randomized study and final numbers in each group is double that of the original cohort? How does surgeon experience/case volume impact results since there was a change in practice? This is not a prospective study design.

Statistical analysis: needs review. Would be nice to see multivariable analysis, role of prostate size, amount of LA used on pain score.

Comments on the Quality of English Language

adequate

Author Response

• Reviewer 2: Study design: Patients who could not tolerate the procedure should not be excluded from the study since the goal of the study is to assess pain and
  • Thank you for this comment. Three patients were excluded because they could not tolerate the TP biopsy under local anesthetic due to anxiety, anal spasm, and anastomosis (see Figure 2). They were assessed this by an experienced surgeon. As such, no data was collected with these patients beyond that the procedure had to be stopped. Had these patients completed the survey, we agree it would be appropriate for their results to be included.

• Reviewer 2: No standardization of dose of LA used.
  • Thank you for this comment. The absence of a standardized LA volume is a limitation of this study. The dose of LA used was based on an experienced surgeon’s clinical expertise to achieve appropriate analgesia during TP biopsy. The surgeon performing the biopsies is highly experienced with this procedure and accounted for factors including patient size and biopsy target when achieving appropriate analgesia. While there was no standardized dose of LA given, the amount of LA required to achieve analgesia was measured per patient and we have now amended table 1 to reflect the average and median LA used per group.

• Reviewer 2: Figure 2 is misleading, this is not a randomized study and final numbers in each group is double that of the original cohort?
  • Thank you for this comment. The absence of randomization is a limitation of this study. This project began as a quality improvement audit and collected data for the control arm. The project later expanded to include an intervention group and data collection began after most of data belonging to the control arm was collected. Future studies could consider randomizing participants to strengthen the evidence. We have now amended figure 2 to the following:

• Reviewer 2: How does surgeon experience/case volume impact results since there was
  a change in practice? This is not a prospective study design.

Thank you for this comment. All biopsies were taken by the same surgeon who is subspecialized in the field and highly experienced with this procedure. The case volume would not have had any meaningful impact on the results as the surgeon regularly performs TP biopsies and there was no change in technique between the two groups outside the introduction of over-the-counter analgesia prior to the procedure in the intervention group. We have amended the manuscript to remove that it is a prospective design.

• Reviewer 2: Statistical analysis: needs review. Would be nice to see multivariable analysis, role of prostate size, amount of LA used on pain score.

Thank you for this comment. We agree a multivariable analysis would be ideal but did not conduct it because we believed it would demonstrate a meaningful difference in our results given the weak associations we saw between prostate size and pain levels.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The authors assessed pain level using a well-accepted tool, the Visual Analog Score. They demonstrated that there was no significant impact of adding over the counter analgesics to local anesthesia in decreasing pain level at the time of trasperineal prostate biopsy.

Author Response

Thank you.

Reviewer 4 Report

Comments and Suggestions for Authors

So the TP biopsy has previously showed infection and sepsis benefit and now even the analgesia free peri-procedure is feasible. 
authors should reference PREVENT trial in their discussion.

Author Response

• Reviewer 4: Reference PREVENT trial in discussion.
  • Thank you for this comment. This has now been added.