Round 1

Reviewer 1 Report

Thank you for inviting me to review the article titled “Is it safe to switch from a standard anterior to Retzius-sparing approach in robot-assisted radical prostatectomy?

The authors evaluate the safety and feasibility of RS-RARP to standard RARP by comparing 100 prospective RS-RARP cases to a historical cohort of 100 standard RARP patients.

Comments:

1.     It would have been interesting to see both the approach and their follow-up prospectively.

2.     Both pathologic T stage and LVI seemed to have increased risk of biochemical recurrence in the multivariate analysis

3.     Limitations are appropriately mentioned in the discussion

Author Response

We would like to thank the reviewers for their thorough evaluation of our manuscript and constructive feedback.

We would like to respond to the reviewers:

Thank you for inviting me to review the article titled “Is it safe to switch from a standard anterior to Retzius-sparing approach in robot-assisted radical prostatectomy?

The authors evaluate the safety and feasibility of RS-RARP to standard RARP by comparing 100 prospective RS-RARP cases to a historical cohort of 100 standard RARP patients.

• It would have been interesting to see both the approach and their follow-up prospectively.

Response: We would like to thank the reviewer for his/her comment. Although the data of RS-RARP patients were collected and evaluated prospectively, the SA-RARP data were evaluated retrospectively. We agree that this is a limitation of our study, as this comes with bias and missing data, which may have an influence on data analysis. Therefore, we added the following paragraph to the limitations section in the discussion: “Firstly, this is a non-randomized study which is prone to bias. Patients with tumours close to the bladder neck or in the anterior part of the prostate were actively withheld from inclusion in the RS-RARP group. This selection bias may compromise the generalizability of the results of this study. Furthermore, the retrospective analysis of the SA-RARP data is inextricably linked to a certain level of bias in which missing data may have affected data analysis.”

• Both pathologic T stage and LVI seemed to have increased risk of biochemical recurrence in the multivariate analysis

Response: We would like to thank the reviewer for his/her remark. To evaluate predictors for biochemical recurrence after RS-RARP, a univariate and multivariate logistic regression analysis were performed in the RS-RARP group. Only those covariates that showed statistical significance in univariate regression were selected for multivariate logistic regression. The results of the multivariate logistic regression analysis are shown in table 5. As the level for statistical significance was set at p < 0.05 before the start of the analysis, only the pathological T-stage can be considered an independent predictor for biochemical recurrence after RS-RARP, as it was the only covariate with p < 0.05. Lymphovascular invasion had a p value of 0.066 and was thus considered not to be statistically significant.

• Limitations are appropriately mentioned in the discussion

Response: We would like to thank the reviewer for this kind remark.

Reviewer 2 Report

This case report was described the utility of Retzius-sparing RARP in patients with prostate cancer. Overall, the reviewer thinks that this study does not seem to demonstrate a high level of surgical skill. The reviewer would like to suggest some critiques as follows.

1.     First, the authors should follow the journal style indicated in the instructions, especially the method of citation and the Reference sections.

2.     On line 17,”standard anterior RARP” is correct? Standard RARP with anterior approach is better? Please revise all similar sections.

3.     On line 25, “p=0.292” is wrong. “p = 0.292” is correct. Please revise all similar sections.

4.     On line 29, the reviewer thinks that the follow-up period is too short to discuss postoperative BCR.

5.     Is the reason for the large number of patients with RM positive a technical problem? The authors mentioned that there are many cases of locally advanced PCa, however, are there any problems with the indications for surgery?

6.     On line 85, “The standard hospital duration” is correct?

7.     The reviewer thinks the recurrence rate is too high in the third month after surgery. Defining postoperative recurrence as PSA >0.2 ng/mL is normal and not particularly strict.

Author Response

We would like to thank the reviewer for his/her thorough evaluation of our manuscript and constructive feedback.

We would like to respond to the reviewer:

This case report was described the utility of Retzius-sparing RARP in patients with prostate cancer. Overall, the reviewer thinks that this study does not seem to demonstrate a high level of surgical skill. The reviewer would like to suggest some critiques as follows.

• First, the authors should follow the journal style indicated in the instructions, especially the method of citation and the Reference sections.

Response: We would like to thank the reviewer for his/her comment. All citations and references were changed according to the journal style. All references in the manuscript are now numbered with square brackets “[…]” instead of round brackets “(…)”. All references were changed to the requested format. The word count of the manuscript increased to 4920 words after revisions.

• On line 17,”standard anterior RARP” is correct? Standard RARP with anterior approach is better? Please revise all similar sections.

Response: We would like to thank the reviewer for his/her comment. However, we believe that ‘standard anterior RARP’ is indeed correct. Robot-assisted radical prostatectomy has typically been performed by detaching the bladder from the abdominal wall and by opening the space of Retzius. This technique has been called the ‘standard’ or ‘conventional’ radical prostatectomy in literature [1,2] as the technique was first described like this by Binder, et al. in 2002 [3]. The European Association of Urology guidelines state that “Robot-assisted radical prostatectomy has typically been performed via the anterior approach” [4].

These facts taken into account, we believe that the terms ‘standard anterior RARP’ or ‘standard RARP with anterior approach’ mean the same thing in se. By adding ‘anterior’ to ‘standard RARP’, we just aim to stress the opposite approaches when comparing the standard and Retzius-sparing approaches. We believe that ‘standard RARP with anterior approach’ would decrease the readability of the paper without adding any information to the reader. Therefore, we opted not to change ‘standard anterior RARP’ to ‘standard RARP with anterior approach’. We hope the reviewer can understand our reasoning.

• On line 25, “p=0.292” is wrong. “p= 0.292” is correct. Please revise all similar sections.

Response: We would like to thank the reviewer for his/her remark. We changed the way p values were reported throughout the complete manuscript to the requested style.

• On line 29, the reviewer thinks that the follow-up period is too short to discuss postoperative BCR.

Response: We would like to thank the reviewer for his/her comment. On line 29, we report the 1-year biochemical recurrence free survival (BCR-FS). As the median follow-up is 22 months in the RS-RARP group and 24.5 months in the SA-RARP group, the follow-up is sufficiently long to report the 12-month BCR-FS. In order to clarify the fact that the follow-up period is not too short to discuss the postoperative BCR, we added the number of patients at risk to the BCR-FS Kaplan Meier chart (figure 2).

However, we do agree that a median follow-up of 2 years is a short-term oncological follow-up and that longer follow-up is warranted.

• Is the reason for the large number of patients with RM positive a technical problem? The authors mentioned that there are many cases of locally advanced PCa, however, are there any problems with the indications for surgery?

Response: We would like to thank the reviewer for his/her comment. We assume that with ‘RM positive’, the reviewer means positive surgical margins. As already discussed in the discussion section of the manuscript, there are several different explanations for the relatively high number of positive surgical margins. The surgical learning curve definitely has an impact on the surgical margins. However, this is a fact that occurs with every new surgical technique. Similarly, also in SA-RARP the number of positive surgical margins is subject to the learning curve, as the Swedish LAPPRO trial clearly demonstrated that annual caseload has a significant impact on oncological outcomes of RALP [5].

Apart from the learning curve, also the high number of locally advanced prostate cancer cases included in this study cohort influence the number of positive surgical margins. The reason for this high number of locally advanced and high risk prostate cancer patients is that we are a tertiary referral center where patients with locally advanced disease are seen and treated on a weekly basis.

The EAU guidelines state that radical prostatectomy should be offered to selected patients with locally advanced prostate cancer as part of multi-modal therapy (strong recommendation) [6]. In our center, all prostate cancer patients are counseled extensively about all therapeutic options for their specific disease stage. Patients with locally advanced prostate cancer are thus counseled for radiotherapy + antihormonal treatment or surgery as part of a multimodality treatment.

Therefore, we can safely say that there is no problem with the indication for surgery for the patients included in this study.

• On line 85, “The standard hospital duration” is correct?

Response: We would like to thank the reviewer for his/her comment. We agree that the phrasing “standard hospital duration” may seem odd. The purpose of this sentence was to clarify that the postoperative course after robot-assisted radical prostatectomy is fairly standardized. In our center, the patient remains hospitalized until the time of bladder catheter removal. In case of an uncomplicated intra- and postoperative course, the bladder catheter is removed standardly on postoperative day 3, preceded by cystography in case of an intraoperative positive leak test. In case of normal micturition after catheter removal, the patient can leave the hospital on day 3.

To clearify the postoperative policy to the readers, we added the following paragraph to the “materials and methods” section: “In our center, the postoperative policy after both RS-RARP and SA-RARP follows a standardized protocol in which the patient remains hospitalized until the time of bladder catheter removal. The urinary catheter is removed on postoperative day 3 without cystography in case of a negative intraoperative leakage test. When the intraoperative leakage test is positive, a cystography is performed on postoperative day 3. The urinary catheter is only removed when this cystography shows a watertight vesicourethral anastomosis.- In case of normal micturition after catheter removal, the patient can leave the hospital on postoperative day 3.”

• The reviewer thinks the recurrence rate is too high in the third month after surgery. Defining postoperative recurrence as PSA >0.2 ng/mL is normal and not particularly strict.

Response: We would like to thank the reviewer for his/her comment. However, it is not entirely clear to us what the reviewer is referring to. Based on the Kaplan Meier chart showing biochemical recurrence-free survival (BCR-FS, figure 2), we cannot conclude that there is a higher number of biochemical recurrences in the third month after surgery compared to any other timepoint after surgery. We observe a gradual decrease in BCR-FS that is not significantly different between the RS-RARP and SA-RARP groups.

Possibly, the reviewer is referring to the number of patients with undetectable PSA 3 months after radical prostatectomy. In both the SA-RARP and RS-RARP groups, 15% of patients had a detectable PSA 3 months after surgery. Part of these patients had persistent PSA after surgery, another part developed a biochemical recurrence within 3 months after surgery after the PSA became undetectable. We agree that 15% is high, but again, we must stress the high number of locally advanced and high risk tumours included in this study. As mentioned in the discussion section, other case series with high risk prostate cancer cohorts reported similar biochemical recurrence results at similar follow-up. Furthermore, the fact that there is no significant difference between BCR-FS between the two surgical techniques may imply that the high percentage of 15% of patients with detectable PSA at month 3 is more disease-related than related to the surgical approach.

We agree that a PSA-threshold >0.2 ng/mL is a generally accepted definition of biochemical recurrence after radical prostatectomy for prostate cancer, which is used in many published papers. However, the EAU guidelines state that the decision for salvage treatment after radical prostatectomy for PSA-only recurrence should not be based on a specific PSA-threshold. Once the decision for salvage radiotherapy has been made, it should be administered as soon as possible [6]. Therefore, at our institution, three consecutive rises in PSA after radical prostatectomy are considered a biochemical recurrence, even if the PSA did not reach the 0.20 ng/mL threshold yet (for example: Radical prostatectomy à PSA undetectable à PSA 0.04 à PSA 0.06 à PSA 0.07 à Salvage radiotherapy). Therefore, our definition of ‘biochemical recurrence’ is more strict than in many other published studies. We explained this in the ‘materials and methods’ section, lines 107-109, and discussed this in the ‘discussion’ section, lines 269-271. We hope this explanation can put the reviewer's reservations in perspective.

References:

[1]         Umari, P.; Eden, C.; Cahill, D.; Rizzo, M.; Eden, D.; Sooriakumaran, P. Retzius-Sparing versus Standard Robot-Assisted Radical Prostatectomy: A Comparative Prospective Study of Nearly 500 Patients. J. Urol., 2021, 205, 780–790.

[2]         Galfano, A.; Secco, S.; Dell’Oglio, P.; Rha, K.; Eden, C.; Fransis, K.; Sooriakumaran, P.; De La Muela, P.S.; Kowalczyk, K.; Miyagawa, T.; Assenmacher, C.; Matsubara, A.; Chiu, K.Y.; Boylu, U.; Lee, H.; Bocciardi, A.M. Retzius-Sparing Robot-Assisted Radical Prostatectomy: Early Learning Curve Experience in Three Continents. BJU Int., 2021, 127, 412–417.

[3]         Binder, J.; Jones, J.; Bentas, W.; Wolfram, M.; Bräutigam, R.; Probst, M.; Kramer, W.; Jonas, D. Roboterunterstützte Laparoskopie in Der Urologie Radikale Prostatektomie Und Rekonstruktive Retroperitoneale Eingriffe. Der Urol. A, 2002, 41, 144–149.

[4]         Mottet, N.; van den Bergh, R.C.N.; Briers, E.; Van den Broeck, T.; Cumberbatch, M.G.; De Santis, M.; Fanti, S.; Fossati, N.; Gandaglia, G.; Gillessen, S.; Grivas, N.; Grummet, J.; Henry, A.M.; van der Kwast, T.H.; Lam, T.B.; Lardas, M.; Liew, M.; Mason, M.D.; Moris, L.; Oprea-Lager, D.E.; van der Poel, H.G.; Rouvière, O.; Schoots, I.G.; Tilki, D.; Wiegel, T.; Willemse, P.P.M.; Cornford, P. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer—2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. European Urology, 2021, 79.

[5]         Nyberg, M.; Sjoberg, D.D.; Carlsson, S. V.; Wilderäng, U.; Carlsson, S.; Stranne, J.; Wiklund, P.; Steineck, G.; Haglind, E.; Hugosson, J.; Bjartell, A. Surgeon Heterogeneity Significantly Affects Functional and Oncological Outcomes after Radical Prostatectomy in the Swedish LAPPRO Trial. BJU Int., 2021, 127, 361–368.

[6]         Cornford, P.; van den Bergh, R.C.N.; Briers, E.; Van den Broeck, T.; Cumberbatch, M.G.; De Santis, M.; Fanti, S.; Fossati, N.; Gandaglia, G.; Gillessen, S.; Grivas, N.; Grummet, J.; Henry, A.M.; der Kwast, T.H. van; Lam, T.B.; Lardas, M.; Liew, M.; Mason, M.D.; Moris, L.; Oprea-Lager, D.E.; der Poel, H.G. van; Rouvière, O.; Schoots, I.G.; Tilki, D.; Wiegel, T.; Willemse, P.-P.M.; Mottet, N. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II—2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur. Urol., 2021, 79, 263–282.

Reviewer 3 Report

General comment

The manuscript entitled “Is it safe to switch from a standard anterior to Retzius-sparing approach in robot assisted radical prostatectomy?” aims to assess the feasibility and safety of implementing Retzius-sparing RARP in a tertiary center proposing a comparison with SA-RARP. The manuscript is overall fairly well written and few corrections are required before considering the work publishable. Nevertheless, few major concerns have to be addressed. In detail:

INTRODUCTION

Briefly report differences among the RS and SA RARP

MATERIALS AND METHODS

71: although you reported the reference explaining your procedure, briefly recall the main steps.

85: Considering the relative low number of cases with RS-RARP, removal of urinary catheter at the third post operative day would not be too precocious?

95: how did you assess erectile function (IIEF-5)?

RESULTS

Missing data should be reported as limitations in the discussion.

DISCUSSION

Albeit most of results obtained are discussed in this paragraph, comparison with similar studies should be extended.

Author Response

We would like to thank the reviewer for his/her thorough evaluation of our manuscript and constructive feedback.

We would like to respond to the reviewer:

The manuscript entitled “Is it safe to switch from a standard anterior to Retzius-sparing approach in robot assisted radical prostatectomy?” aims to assess the feasibility and safety of implementing Retzius-sparing RARP in a tertiary center proposing a comparison with SA-RARP. The manuscript is overall fairly well written and few corrections are required before considering the work publishable. Nevertheless, few major concerns have to be addressed. In detail:

• INTRODUCTION
  Briefly report differences among the RS and SA RARP

Response: We would like to thank the reviewer for his/her remark. As requested, we explained the differences between RS-RARP and SA-RARP more in detail in the introduction section. Differences in functional outcomes had already been addressed in detail in the introduction section. We added the following paragraph to the introduction: “In comparison to SA-RARP, Santorini’s plexus, the endopelvic fascia, puboprostatic/pubovesical ligaments and detrusor apron remain intact in RS-RARP.”

• MATERIALS AND METHODS

Although you reported the reference explaining your procedure, briefly recall the main steps.

Response: We would like to thank the reviewer for this comment. As requested, we added a brief description of the surgical steps of the RS-RARP procedure to the ‘materials and methods’ section. We added the following paragraph: “In brief, the RS-RARP procedure starts with the incision of the peritoneum above the vasa deferentes up until the Douglas pouch, where the peritoneal fold is incised. The vasa deferentes are dissected and cut at the tip of the seminal vesicles. Denonvilliers’ fascia is peeled off of the seminal vesicles and they are dissected completely. The lateral side of the prostate is dissected by retracting the seminal vesicles medially. To facilitate access to the prostate and bladder neck, stay sutures are placed on the upper part of the peritoneal incision by use of a straight needle which is placed through the abdominal wall. For a nerve sparing approach, a plane is created between Denonvilliers’ fascia and the prostatic fascia up to the apex of the prostate. The neurovascular bundle is peeled off of the prostatic fascia laterally by blunt dissection. The prostatic pedicle is then clipped and transected. This plane is followed anteriorly and the bladder is peeled from the prostate. Bladder neck dissection starts at its posterior side, just anteriorly of the seminal vesicles and the bladder neck is isoltaed. After bladder neck transection, 2 marking sutures are placed at 6 and 12 o’clock at the bladder neck to evert the mucosa and aid in vesico-urethral anastomosis. The anterior surface of the prostate is dissected, sparing the Santorini's plexus, the puboprostatic/pubovesical ligaments and the Retzius space. The dissection continues apically with transection of the urethra. A vesicourethral anastomosis is performed with two barbed sutures, starting at the 12 o’ clock position on the bladder neck and ending at the 6 o’ clock position on the urethra after complete and watertight approximation of the bladder neck and urethra. After a leak test is performed, the peritoneal incision is closed using a barbed suture.”

• Considering the relative low number of cases with RS-RARP, removal of urinary catheter at the third post operative day would not be too precocious?

Response: We would like to thank the reviewer for his/her question. As mentioned in the paper, an intraoperative leakage test was performed during each surgical intervention. When there was no intraoperative leak, the urinary catheter was removed at the third postoperative day (without cystography). In cases of a positive intraoperative leakage test, a cystography was performed on day 3 after surgery. If this cystography was negative, the catheter was removed on the same day (so also day 3 after surgery). There was thus not one patient in which the catheter was removed without knowing if the vesicourethral anastomosis was waterproof. Therefore we believe that the removal of the catheter on the third day should not be considered precocious.

In order to make this more clear to the reader of this paper, we changed this paragraph in the methods section to: “The urinary catheter is removed on postoperative day 3 without cystography in case of a negative intraoperative leakage test. When the intraoperative leakage test is positive, a cystography is performed on postoperative day 3. The urinary catheter is only removed when this cystography shows a watertight vesicourethral anastomosis.”

• How did you assess erectile function (IIEF-5)?

Response: We would like to thank the reviewer for his/her question. Erectile function was evaluated by questioning of the patient at each follow-up visit after surgery. The patients were asked whether they had had spontaneous or medicinally assisted erections, if the erections were satisfying, if the erections were firm enough for penetrative intercourse and how long the erection lasted. If medication was used, the influence of the medication on erectile function was discussed. However, validated questionnaires such as IIEF-5 were not used to evaluate the erectile function of the patients. We agree that this is an important detail that should be mentioned in the paper. Therefore, we added this to the methods section: “Postoperative erectile function was assessed by questioning of the patient at each follow-up visit and was categorized as potent….”

• RESULTS
  Missing data should be reported as limitations in the discussion.

 Response: We would like to thank the reviewer for his/her comment. Although we believe that the number of missing data in this study is limited, we agree that the retrospective nature of the analysis of the SA-RARP data comes with inherent bias and missing data. Therefore, we added this to the limitations paragraph in the discussion section: “Furthermore, the retrospective analysis of the SA-RARP data is inextricably linked to a certain level of bias in which missing data can affect the analysis of the data.”

• DISCUSSION
  Albeit most of results obtained are discussed in this paragraph, comparison with similar studies should be extended.

 Response: We would like to thank the reviewer for his/her comment. We added a paragraph to the discussion section in which all relevant studies in which RS-RARP and SA-RARP are compared are briefly discussed:

“Different randomized controlled trials reported on a head-to-head comparison of the SA-RARP and RS-RARP techniques. Asimakopoulos, et al. [7][18][16][8] compared 201 SA-RARP to 28 RS-RARP patients. Immediate urinary continence was higher in the RS-RARP group (70.4% vs 58.1%, p = 0.02). PSMs were reported in 15.6% and 13.9% of RS-RARP and SA-RARP respectively (p = 0.600) with 33.7% and 20.3% of PSMs in pT3 patients respectively (p = 0.254)

Lim, et al. [17] compared data of 50 RS-RARP patients with 50 SA-RARP patients after propensity-score matching. They reported an overall PSM rate of 14% in both RS-RARP and SA-RARP patients (p = 1.00) and a PSM rate in pT3 disease of 41.7% and 22.2% for RS-RARP and SA-RARP respectively (p = 0.64). At 4 weeks postoperatively, 70% of RS-RARP patients and 50% of SA-RARP patients were continent (p = 0.04). Lee, et al. [33], compared data of 609 RS-RARP patients with 609 SA-RARP patients after propensity-score matching. No significant differences in complications or PSMs were observed between both groups. The continence rates at 1 month postoperatively were 45% and 9.0% in the RS-RARP and SA-RARP groups respectively, which rose to 98% and 77% by month six postoperatively (p < 0.001)

Egan, et al. [20] evaluated results of 140 consecutive RARPs (70 SA-RARP + 70 RS-RARP). No significant difference in complications was observed. At 12 months postoperatively, 97.6% and 81.4% of patients in the RS-RARP and SA-RARP groups respectively were continent (p = 0.002). The time to continence recovery was significantly faster in the RS-RARP group (44 vs 131 days, p < 0.001). Positive surgical margins were observed in 34.3% and 30.0% of RS-RARP and SA-RARP patients respectively (p = 0.590) with BCR occuring in 12.9% and 18.6% of patients in the RS-RARP and SA-RARP groups respectively (p = 0.357). However, median follow-up of RS-RARP patients was significantly shorter reaching only 12.3 months.

Anil, et al. [34] reported data of a cohort of 50 RS-RARP and 50 SA-RARP patients and retrospectively assessed the safety of the switch from an anterior to posterior approach. They did not report a significant difference in erectile function recovery, early urinary continence recovery, continence recovery at 1 year postoperatively or positive surgical margins. Biochemical recurrence was observed in 14% and 12% of RS-RARP and SA-RARP patients respectively (p = 0.766). Remarkably, no cT3 tumors were included in this study.”

Reviewer 4 Report

Dear authors,

This is a very important study to ensure a superior quality of life for patients with prostate cancer after surgery. Of course, this must be ensured under conditions of maximum safety for the patient's life, and the current study demonstrates the superiority of RS-RARP over SA-RARP, at least in terms of the continence. Also, with the ascent on the learning curve, I am sure that the results will be improved in terms of the other compared aspects. Once the limitations of the study have been mentioned, including the relatively small number of patients, I think the article can be published. I just have a little suggestion: -Line 266-269 - This phrase is not academic, I suggest you delete it or reformulate it. 

Author Response

We would like to thank the reviewer for his/her thorough evaluation of our manuscript and constructive feedback.

We would like to respond to the reviewer:

• This is a very important study to ensure a superior quality of life for patients with prostate cancer after surgery. Of course, this must be ensured under conditions of maximum safety for the patient's life, and the current study demonstrates the superiority of RS-RARP over SA-RARP, at least in terms of the continence. Also, with the ascent on the learning curve, I am sure that the results will be improved in terms of the other compared aspects. 

Response: We would like to thank the reviewer for his/her kind remark.

• Once the limitations of the study have been mentioned, including the relatively small number of patients, I think the article can be published.

Response: We would like to thank the reviewer for his/her comment. We agree that the sample size of the study is not extremely large. Therefore, we added this to the limitations paragraph in the discussion. The last phrase of the limitations paragraph was changed to: “Finally, this is a single institution evaluation from a tertiary center with a relatively small sample size, which may influence the generalizability of the results.”

• I just have a little suggestion: -Line 266-269 - This phrase is not academic, I suggest you delete it or reformulate it. 

Response: We would like to thank the reviewer for his/her comment. We agree with the comment of the reviewer. Therefore, we rephrased this paragraph: “Secondly, we hypothesize that a proportion of the positive surgical margins, as described in the pathology reports, may have been false positive due to tears in the prostatic capsule caused by intraoperative traction. In such cases, a ‘positive’ surgical margin would not have led to tumour tissue remaining in the surgical field, thus not resulting in biochemical recurrence.”

Round 2

Reviewer 2 Report

I think it is carefully revised, but I disagree with some parts of it.

The authors state that the high rate of positive margins is due to the high number of locally advanced cancers, but is this a problem for the indication for surgery?

Author Response

We would like to thank the reviewer for his/her thorough evaluation of our manuscript and his/her critical feedback.

We would like to respond to the reviewer:

• I think it is carefully revised, but I disagree with some parts of it.

The authors state that the high rate of positive margins is due to the high number of locally advanced cancers, but is this a problem for the indication for surgery?

Response: We would like to thank the reviewer for this comment. Since we already addressed this question extensively in review round 1, we assume that the reviewer was not satisfied with our answer.

Firstly, we would like to answer the question to why the positive surgical margin rate is relatively high more clearly.

Apart from the surgical learning curve and the high number of locally advanced cases (as discussed previously), also the importance of correct preoperative staging has to be taken into account when evaluating surgical margins. MRI plays a central role in the assessment and staging of prostate cancer patients. The preoperative MRI guides a surgeon in his surgical planning, the degree of nerve sparing and the extent to which he will dissect closely to the prostate capsule. A lot depends on the correct interpretation of the MRI by the radiologist.

Of all patients who underwent RS-RARP in our study, MRI data were available for 99% of patients. As described in table 1, an iT3 lesion was described by the radiologist in 26% of patients in the RS-RARP group. However, on final pathology 48% of the RS-RARP patients proved to have a pT3 tumor. This discordance between the preoperative staging and the final pathology results plays an important role in the incidence of positive surgical margins, as surgeons tend to dissect more closely to the prostate capsule if organ confined disease is expected.

This raises the question whether our local radiologists are insufficiently trained to interpret prostate MRIs. However, we can say in good conscience that this is absolutely not the case. MRI is just not a flawless tool to predict locally advanced disease. A meta-analysis of de Rooij, et al. [1] demonstrated that the sensitivity of MRI to detect locally advanced disease is rather low. The sensitivity for detection of extracapsular extension was 0.57 (95% CI 0.49-0.64), for seminal vesical invasion 0.61 (95% CIU 0.54-0.67) and for overall stage T3 detection 0.58 (95% CI 0.47-0.68).

Thus, in conclusion, locally advanced disease is rather difficult to predict and therefore positive surgical margins may occur in cases where the surgeon did not expect locally advanced disease based on the preoperative MRI.

Now we come to the specific question of the reviewer: Is the high surgical margin rate a problem for the indication for surgery? We assume the reviewer raises the question whether patients with T3 tumors should be considered for radical prostatectomy (RP) or should they be treated with alternative treatment options such as a combination of external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT).

Patients with locally advanced prostate cancer experience a clear survival benefit after local curative treatment, but there is still no consensus on the optimal treatment option [2]. There is evidence from randomized trials for a survival benefit of surgery in localized prostate cancer, and data from observational cohorts support radical prostatectomy as treatment for locally advanced disease [3].

Different nonrandomized studies comparing RP to EBRT + ADT for high risk localized and locally advanced prostate cancer reported a benefit in overall survival and cancer-specific survival of 10-28% and 4-8% respectively at 10 years follow-up favoring RP [2]. However, there is no randomized controlled trial yet comparing primary surgery with primary radiotherapy for men with locally advanced prostate cancer. However, the SPCG-15 trial will answer this question [4].

Tilki, et al. [5] reported on a prospective but non-randomized study comparing the multimodality treatment RP + adjuvant EBRT + ADT to EBRT + brachytherapy + ADT. The authors reported no significant difference in the risk of prostate cancer-specific or all cause mortality between both groups.

Also the EAU guidelines state that radical prostatectomy should be offered to selected patients with locally advanced prostate cancer as part of multi-modal therapy (strong recommendation) [6].

Based on the GETUG-AFU 17 [7], RAVES [8] and RADICALS [9] trials, we know that patients treated with salvage radiotherapy at time of biochemical recurrence have the same progression free survival as patients treated with adjuvant radiotherapy.

Based on the above mentioned facts, patients with locally advanced prostate cancer may be treated surgically, as long as they are well informed that the treatment is part of a multimodality treatment program. However, these patients should not standardly receive adjuvant EBRT + ADT, but only receive salvage radiotherapy + ADT in case of biochemical recurrence.  If these patients do not show a biochemical recurrence, they may be spared from a possibly unnecessary adjuvant treatment with EBRT and ADT and, thus, may be spared from the possible side-effects that come with these treatments.

Based on all these findings, we believe it is reasonable to state that there is no problem with the indication for surgery for the patients included in this study.

References:

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2. Moris L, Cumberbatch MG, Van den Broeck T, Gandaglia G, Fossati N, Kelly B, Pal R, Briers E, Cornford P, De Santis M, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol, 2020, 77, 614-627. doi: 10.1016/j.eururo.2020.01.033
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Reviewer 3 Report

The authors improved the manuscript according to previous suggestion. Nevertheless, I would add in the limitations the lack of erectile function testing via IIEF-5

Author Response

We would like to thank the reviewer for his/her thorough evaluation of our manuscript and his/her critical feedback.

We would like to respond to the reviewer:

1) The authors improved the manuscript according to previous suggestion.

Response: We would like to thank the reviewer for his/her kind remark.

2) Nevertheless, I would add in the limitations the lack of erectile function testing via IIEF-5

Response: We would like to thank the reviewer for this comment. We agree that the absence of validated questionnaires to evaluate the erectile function of patients after radical prostatectomy is a limitation of this study. Therefore, we added this to the limitation paragraph in the discussion section:

"Thirldy, erectile function was evaluated by questioning patients at each follow-up visit. However, validated questionnaires were not used to asses erectile function, which may have influenced the erectile function outcome assessment."

Round 3

Reviewer 2 Report

none