Selection of patients for nerve sparing surgery in robot‐assisted radical prostatectomy

Abstract Context Robot‐assisted radical prostatectomy (RARP) has become the standard surgical procedure for localized prostate‐cancer (PCa). Nerve‐sparing surgery (NSS) during RARP has been associated with improved erectile function and continence rates after surgery. However, it remains unclear what are the most appropriate indications for NSS. Objective The objective of this study is to systematically review the available parameters for selection of patients for NSS. The weight of different clinical variables, multiparametric magnetic‐resonance‐imaging (mpMRI) findings, and the impact of multiparametric‐nomograms in the decision‐making process on (side‐specific) NSS were assessed. Evidence acquisition This systematic review searched relevant databases and included studies performed from January 2000 until December 2020 and recruited a total of 15 840 PCa patients. Studies were assessed that defined criteria for (side‐specific) NSS and associated them with oncological safety and/or functional outcomes. Risk of bias assessment was performed. Evidence synthesis Nineteen articles were eligible for full‐text review. NSS is primarily recommended in men with adequate erectile function, and with low‐risk of extracapsular extension (ECE) on the side‐of NSS. Separate clinical and radiological variables have low accuracy for predicting ECE, whereas nomograms optimize the risk‐stratification and decision‐making process to perform or to refrain from NSS when oncological safety (organ‐confined disease, PSM rates) and functional outcomes (erectile function and continence rates) were assessed. Conclusions Consensus exists that patients who are at high risk of ECE should refrain from NSS. Several multiparametric preoperative nomograms were developed to predict ECE with increased accuracy compared with single clinical, pathological, or radiological variables, but controversy exists on risk thresholds and decision rules on a conservative versus a less‐conservative surgical approach. An individual clinical judgment on the possibilities of NSS set against the risks of ECE is warranted. Patient summary NSS is aimed at sparing the nerves responsible for erection. NSS may lead to unfavorable tumor control if the risk of capsule penetration is high. Nomograms predicting extraprostatic tumor‐growth are probably most helpful.

Patient summary: NSS is aimed at sparing the nerves responsible for erection. NSS may lead to unfavorable tumor control if the risk of capsule penetration is high.
Nomograms predicting extraprostatic tumor-growth are probably most helpful.

K E Y W O R D S
erectile dysfunction, evidence synthesis, nerve-sparing, prostate cancer, radical prostatectomy, systematic review

| INTRODUCTION
Robot-assisted radical prostatectomy (RARP) has shown excellent oncologic outcomes for men with localized prostate cancer (PCa) but carries a substantial risk of urinary incontinence and erectile dysfunction. [1][2][3][4] A key determinant of functional outcome is the preservation of the neurovascular bundle (NVB) at the time of surgery. The NVB is a poorly defined anatomical structure that runs along the dorsolateral side of the prostate. 5,6 It is functionally related to the autonomic nervous system and innervates the corpora cavernosa but has also been associated with the innervation of the external sphincter complex.
Preserving the NVB in men undergoing RARP has been related to improved postoperative erectile function and improved urinary continence rates the first months after surgery compared with those not undergoing nerve-sparing surgery (NSS). [1][2][3][4][5][6][7][8] A concern with NSS is that close surgical preparation along the prostatic capsule may inadvertently lead to a positive surgical margin (PSM) and potentially a noncurative resection. Several studies have documented the negative impact of PSM on biochemical recurrence after RARP. 1,2,9 The risk of a PSM seems most present when extracapsular tumor extension (ECE) exists. 10 Therefore, urological surgeons are reluctant to perform NSS close to the prostate when there is a concern and uncertainty about the local extent of the cancer, and this will lead to decreased postoperative functional recovery rates. Surgeons must plan NSS by balancing the competing functional and oncological outcomes. Therefore, it is optimally important to riskstratify patients who opt RARP for (side-specific) NSS or otherwise for a non-NSS approach.
We performed a systematic review of the available literature in which (contra)indications for NSS in patients undergoing RARP were associated with oncological safety and/or functional outcomes. In this, the weight of different clinical variables, multiparametric-magnetic resonance imaging (mpMRI) parameters and of nomograms in the decision-making process on (side-specific) NSS were evaluated.

| Data acquisition and search strategy
A review was performed following the Preferred-Reporting Items for Systematic-Reviews and Meta-Analysis (PRISMA) statement (http:// www.prisma-statement.org). The review protocol was published in the PROSPERO database. 11 Both PubMed and Embase databases were searched for English language articles published from January 2000 until December 2020. Key Search terms included indexed terms (MeSh for PubMed; EMtree for EMBASE) as well as free-text terms.
Terms expressing "prostatectomy" were used in combination with terms comprising "nerve-sparing."

| Screening of abstracts and full-text articles
We first limited our search to abstracts of studies that may be used for inclusion. Full-text original articles were retrieved from the selected abstracts. Abstracts and original articles were independently assessed by two reviewers for eligibility (AV, PvL). Each citation was classified as inclusion, unsure, or exclusion. In case of disagreement, the manuscripts were discussed in a combined session. Agreement was obtained for all included papers. References of all full-text articles were screened to identify additional relevant articles not found in the PubMed, EMBASE, and MEDLINE databases. Secondary publications and (systematic) reviews on a similar subject or with part of the research question as a subject were omitted, as were abstracts without accompanying full-text articles. The final number of included and excluded studies (with the reason for exclusion) is reported in the PRISMA ( Figure 1).

| Eligibility
As proposed by the PRISMA guidelines, we used the Population, Intervention, Comparator, Outcome, and Study (PICOS) design model to direct eligibility. The specific PICO is presented in Table 1. Studies were eligible if they included patients who opted for (robot-assisted) radical prostatectomy for histological proven PCa and mentioned specific (contra)indications for (side-specific) NSS. As primary outcome, it was studied whether the proposed clinical and radiological variables for the (extent of) NSS were associated with oncological safety (organ-confined disease, rates of PSM) without compromising functional outcomes (erectile function and continence rates). Studies reporting on the prediction of ECE or extraprostatic extension (EPE) using preoperative variables only without a recommendation on NSS were excluded. Second, we looked for a change of surgical plan on NSS due to application of mpMRI.

| Data extraction
After full-text evaluation, data from eligible studies were independently extracted by two reviewers. To avoid overlap of patient's populations, if multiple publications reported on the same patient population, the largest study was included. The following data were independently extracted from full-text articles: number of patients, type of study, variables used to determine (side-specific)NSS, and the eventual proposed conditions to perform NSS, and oncological safety and functional outcomes ( Table 2).

| Risk of bias
Risk-of-bias (RoB) assessment was performed using the Cochrane recommendations for RoB assessment of nonrandomized controlled studies (NRS). 12 It comprises the standard Cochrane domains and additionally includes assessment of five key prespecified confounding factors for NRSs. 13,14 Potential subgroup analyses were preplanned based on the following variables: clinical tumor stage, initial prostate-specific antigen (PSA) level, biopsy Gleason score, other biopsy variables, features-on-MRI, nomograms, and algorithm. Two reviewers (AV, PvL) assessed RoB. Disagreement was resolved by discussion.

| RoB and confounding assessment of the included studies
The RoB assessment of all included studies are presented in Figure 2.
RoB and confounding factors were assessed for each study individu-  22 The surgical plan was changed to NSS in 17 out of 28 patients (61%) and to a non-NSS in 11 (39%). In patients whose surgical plan was changed to NSS, there were no PSM on the side of the prostate with a change in treatment plan. continence rates in the first months after RARP, but the studies come to different conclusions for the period after 6 months. [1][2][3][4][5] It has been argued, however, that even early improvement in urinary continence (<3 months after surgery) is enough to perform NSS with respect to the improvement in HRQoL. 49 Therefore, NSS might be performed regardless of potency status. 19 Despite these recommendations, few studies have addressed age and preoperative functions into their predictive models.

| DISCUSSION
In the PCa guidelines of the EAU and American Urological Association (AUA), it is advocated that NSS should be offered to patients with localized PCa undergoing RARP. 44,45 The concept of locally confined versus locally advanced disease, however, is poorly defined.
Commonsensically, one should refrain from NSS in the presence of a tumor that extends through the prostate capsule and grows into the NVB. Sparing the NVB would inevitably lead to a PSM and thereby to biochemical and/or local recurrence of disease. 10 Furthermore, only few of the decision-making tools for EPE have been externally validated within 5 years after development and often perform poor. 34 Adding mpMRI-findings may potentially improve the predictive performance of these nomograms. 70 Though, urological surgeons need to consider the limitations of these decision tools when applying them on their own patients. 34 The efficacy and safety of perioperative Neurovascular Structure Adjacent Frozen Section Examination (NeuroSAFE) is being investigated in RCTs. [71][72][73] Nonrandomized studies have shown that Neuro-SAFE is able to improve NSS rates while it may help to achieve a modest reduction in PSM rates. Functional outcomes and long-term oncological outcomes need to be further explored. However, the establishment of the respective infrastructure to routinely perform the NeuroSAFE investigation intraoperatively is labor intensive and not possible in every institution. Furthermore, the feasibility of 3D imaging techniques and augmented-reality using preoperative mpMRI incorporated into the robotic systems and/or the use of 3D reconstructions and 3D prints of the prostate is investigated and could possibly assist the surgeon into making a proper surgical plan on the side and extent of NSS. 74,75 At last, implementing modern PSMA-PET imaging into predictive nomograms, according to the newly developed e-PSMA guidelines, may be used to predict the side of ECE, increase the rate of (side-specific) NSS, lower PSM rates, and improve functional outcomes even in non-organ-confined disease. 76 This review was performed robustly in accordance with