Robot-assisted radical prostatectomy following holmium laser enucleation of the prostate: perioperative, functional, and oncological outcomes

Robot-assisted radical prostatectomy with previous holmium laser enucleation of the prostate is challenging, and few studies have analyzed its perioperative, functional, and oncological outcomes. Here we retrospectively evaluated 298 robot-assisted radical prostatectomies, including 25 with and 273 without previous holmium laser enucleation of the prostate, performed in 2015–2022. Regarding perioperative outcomes, operative and console times were significantly longer in the previous holmium laser enucleation of the prostate group. In contrast, the estimated blood loss was similar between groups, and there were no transfusions or intraoperative complications. Multivariable Cox hazard regression analysis of the functional outcomes of postoperative urinary continence showed that body mass index, intraoperative bladder neck repair, and nerve sparing were independently associated factors, whereas a history of holmium laser enucleation of the prostate was not. Similarly, a history of holmium laser enucleation of the prostate was not associated with biochemical recurrence; however, positive surgical margins and seminal vesicle invasion were independent risk factors of biochemical recurrence. Our findings revealed that robot-assisted radical prostatectomy after holmium laser enucleation of the prostate was safe and raised no concerns of postoperative urinary incontinence or biochemical recurrence. Therefore, robot-assisted radical prostatectomy may be a treatment option for patients with prostate cancer after holmium laser enucleation of the prostate.


Introduction
Prostate cancer is the primary cause of disease and death in men, with 1.6 million prostate cancer cases and 366,000 deaths annually worldwide [1]. Radical prostatectomy is one of the first treatment choices for localized prostate cancer, with a resultant life expectancy of ≥ 10 years [2]. Robotassisted radical prostatectomy (RARP) was introduced in the 2000s and has become an established surgical procedure.
Several studies have reported improved perioperative and functional outcomes in terms of blood loss, blood transfusion rate, hospital stay duration, nerve sparing, and recovery rate of urinary continence and erectile function compared with open or laparoscopic radical prostatectomy [3,4]. In addition, age, body mass index (BMI), comorbidity index, lower urinary tract symptoms, and prostate volume are factors associated with postoperative urinary continence after RARP [5].
Although RARP is becoming the standard procedure for prostate cancer and its indications are expanding, it remains challenging to perform RARP after surgical treatment of benign prostatic hyperplasia (BPH). Currently, it is important to evaluate the effect of holmium laser enucleation of the prostate (HoLEP) on RARP. HoLEP was first proposed in 1999 for the treatment of BPH [6]. Compared with the conventional surgical procedure for BPH, transurethral resection of the prostate (TUR-P), HoLEP is superior in terms of blood loss and transfusion rate, requires a shorter 1 3 hospital stay, can be performed regardless of prostate volume, and has a lower recurrence rate [7,8]. Therefore, as in Western countries, Japan has recently adopted HoLEP in place of TUR-P. The detection rate of incidental prostate cancer (IPCa) by HoLEP is reportedly 5.9-11.7% [9][10][11][12][13][14][15][16], and a certain number of patients undergo RARP for residual tumors after HoLEP.
There have been previous reports from only one institution on the perioperative results of RARP after HoLEP [17,18]. An initial report of 11 cases indicated that RARP after HoLEP was associated with significantly longer operative time, increased blood loss, and longer time to reach urinary continence than conventional RARP [17]. Subsequently, long-term follow-up and additional cases were reported by the same institution [18]. The surgical time was significantly shorter than in the initial 11 cases, and blood loss was less in the latter 16 cases. In addition, the time to urinary continence was significantly shorter in the latter group. However, the percentage of pad-free patients was significantly lower in the RARP after HoLEP treatment group than in the conventional RARP treatment group, which raised the issue of functional outcomes [18].
Although the number of RARP cases after HoLEP increases as the latter becomes more common, evidence of its safety and perioperative and long-term outcomes has not yet accumulated. Therefore, this study aimed to compare the perioperative, oncological, and functional outcomes of RARP after HoLEP with those of standard RARP in Japanese patients at a single institution.

Setting
This study was conducted at the Jyoban Hospital. Over the past few years, approximately 100 HoLEP and RARP procedures for BPH and prostate cancer, respectively, have been performed annually at our hospital, one of the leading highvolume centers in Japan for urologic, particularly prostate, surgery.

Participants
This study included 298 RARP procedures performed by a single skilled surgeon at Jyoban Hospital between March 2015 and March 2022, of which 25 were on patients who had previously undergone HoLEP. The Institutional Review Board of the Jyoban Hospital of Tokiwa Foundation approved this study (no. JHTF-IRB2021.013) and waived the need for informed consent.

Surgical procedure
Transperitoneal RARP was performed as previously described using a da Vinci Si (Intuitive Surgical, Sunnyvale, CA, USA) from March 2015 to November 2019, and a da Vinci Xi (Intuitive Surgical, Sunnyvale, CA, USA) from December 2019 onward [19][20][21][22]. Nerve sparing was performed using intrafascia and antegrade approaches [23]. When the prostate was separated from the bladder neck and the bladder neck opened wide during RARP, it was repaired before vesicourethral anastomosis. Vesicourethral anastomosis was performed utilizing two 3-0 Monocryl continuous sutures. A 16-French silicon Foley catheter with a 10 mL balloon was placed. The urinary bladder was then filled with 150 mL of normal saline to check for watertight anastomosis.

Outcome measures
The primary outcomes of this study were the rate of urinary continence recovery and biochemical recurrence-free rate after RARP in the previous and no previous HoLEP groups. Perioperative outcomes including operative and console time, blood loss, rate of vesicourethral anastomotic urinary leakage, postoperative hospital stay, and pathological findings including pathological T stage and rate of positive surgical margins (PSM) were also evaluated between the previous and no previous HoLEP groups. Urethral cystography was performed on the seventh postoperative day, and the urethral catheter was removed if there was no vesicourethral anastomotic urinary leakage. The pathological findings were diagnosed and evaluated by a pathologist. For the definition of urinary continence, less than one pad use/day was defined as maintained urinary continence during outpatient visits [5]. After hospital discharge, outpatient follow-up was conducted every 1-3 months, with PSA assays and questioning about the number of pads used.

Data collection
Preoperative information, such as age, BMI, initial prostatespecific antigen (PSA) level, clinical T stage, and Gleason Score (GS), were extracted from the patients' electronic medical records. GS was classified into Gleason-grade groups as defined by the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs 2016, and the percentage of each group was calculated [24]. For patients who underwent HoLEP before RARP, age at HoLEP, PSA level before HoLEP, amount of prostate specimen enucleated, and intervals between HoLEP and RARP were extracted. In addition, perioperative information, including operative time, console time, blood loss, presence or absence of bladder neck repair, nerve sparing and lymph node dissection, prostate weight, duration of urethral catheter placement, presence or absence of vesicourethral anastomotic urinary leakage on urethral cystography, and postoperative hospital stay, were extracted. Furthermore, pathological findings such as pathological T stage, Gleason-grade group of removed prostate, and presence or absence of extracapsular invasion, PSM, vascular invasion, lymphatic invasion, perineural invasion, and seminal vesicle invasion were extracted. Finally, the intervals from RARP until the number of pads dropped below one use per day and biochemical recurrences were extracted. Biochemical recurrence was defined as two consecutive PSA values higher than 0.2 ng/mL and rising after radical prostatectomy [25].

Statistical analysis
Continuous variables are presented as mean and standard deviation (SD) for normally distributed variables and as median and interquartile range (IQR) for non-normally distributed variables. Categorical variables were described as percentages. When examining whether there were significant differences in variables between the two groups, continuous variables were analyzed using the t-test for normally distributed variables or the Wilcoxon rank-sum test for non-normally distributed variables, and categorical variables were analyzed using Pearson's χ-squared test. A p value of 0.05 or less was considered a statistically significant difference. All analyses were performed using Stata version 15.1 (Stata Corp. LP, College Station, TX, USA).

Patient background
Preoperative patient characteristics are shown in Table Table 1 Preoperative variables before robot-assited radial prostatectomy in the two groups HoLEP 1 holmium laser enucleation of the prostate, SD 2 standard deviation, BMI 3 body mass index, PSA 4 prostate-specific antigen,IQR 5 interquartile range,RARP 6 robot-assisted radical prostatectomy

Functional outcome: postoperative urinary continence
The Kaplan-Meier curves in Fig. 1 compares the rate of postoperative urinary continence between the previous and no previous HoLEP groups; the log-rank test showed no statistically significant differences (p = 0.06). In addition, we conducted univariate and multivariate Cox proportional hazards regression analyses to determine the factors related to postoperative urinary continence. Univariate analysis was performed using preoperative and perioperative factors as co-variables including age, BMI, previous HoLEP, bladder neck repair, nerve sparing, and vesicourethral anastomotic urinary leakage at urethral cystography on the seventh postoperative day, and multivariate analysis was performed using the backward method to select variables. Oncological outcome: biochemical recurrence Figure 2 shows the Kaplan-Meier curves of the biochemical recurrence-free rate between the previous and no previous HoLEP groups; the log-rank test showed no statistically significant differences (p = 0.14). We also evaluated the risk factors for biochemical recurrence after RARP using the Cox proportional hazards regression analysis. Initial PSA level, previous HoLEP, and pathological findings were included in the univariate analysis as co-variables, and multivariate analysis was performed using the backward method to select variables. Table 5 presents the results. PSM (HR: 3.53, 95% CI: 1.37-9.08, p = 0.009) and seminal vesicle invasion (HR, 3.03; 95% CI: 1.12-8.14, p = 0.03) were independent risk factors for biochemical recurrence after RARP.

Discussion
Previous HoLEP was not a risk factor for urinary continence or biochemical recurrence after RARP. Furthermore, RARPs with previous HoLEP were performed safely without increased blood loss or intraoperative complications, although the operative and console times were significantly longer than those without previous HoLEP. In our experience, the first challenging step in RARP with previous HoLEP was identifying the bladder neck. It was difficult to accurately identify the space between the anterior bladder wall and the prostate from the outside because of the thinner and softer anterior surface of the prostate due to enucleation of the prostatic transition zone. Second, careful attention was required to dissect the posterior bladder neck because the position of the ureteral orifice was deviated due to long-term BPH, and HoLEP blurred the boundary between the posterior bladder wall, triangle, and prostate, as mentioned in a previous report [13]. The ureteral orifices were not damaged, and preoperative ureteral stenting was not necessary. It was also difficult to enter the correct layer for nerve sparing because of the softer prostatic capsule caused by enucleation of the prostatic transition zone, and greater tissue reaction and periprostatic fibrosis caused by fluid extravasation during HoLEP as well as TUR-P [26]. These difficult procedures and higher rates of bilateral nerve sparing and bladder neck repair resulted longer operative and console times. As mentioned above, these procedures require more advanced surgical skills; however, three-dimensional visualization and seven degrees of freedom with instrument movement  1 Kaplan-Meier curve of the urinary continence rate after robotassisted radical prostatectomy between the previous and no previous holmium laser enucleation of the prostate groups using the da Vinci robotic system may make it possible to perform RARP with the previous HoLEP. In our study, the rate of postoperative urinary continence in the previous HoLEP group was relatively lower than that in the no previous HoLEP group (Fig. 1); however, there was no significant difference between the two groups (p = 0.06). Previous studies also reported that the rates of achieving urinary continence were similar between RARPs with and without previous HoLEPs [17,18]. Moreover, previous HoLEP was not an independent risk factor for postoperative urinary incontinence, whereas a higher BMI, intraoperative bladder neck repair, and nerve sparing were significantly associated in our study. A previous review showed that age, BMI, comorbidity index, lower urinary tract symptoms, and prostate volume were preoperative predictors of urinary incontinence after RARP [5]. And nerve sparing has also proven to be important in recovering postoperative urinary continence [27,28]. Bladder neck repair was performed when the bladder neck was wide after dissection of the bladder neck and prostate. In the group of patients who did not have previous HoLEP, those who underwent bladder neck repair had a significantly larger prostatic weight compared to those without neck repair (59.8 ± 24.2 g vs. 42.1 ± 14.5 g, p = 0.005, data not shown). In other words, previous HoLEP or larger prostatic weight, which were associated with significantly higher rates of intraoperative bladder neck repair, may result in poor postoperative urinary continence.
Regarding pathological findings, 10 out of 25 patients (40%) had no residual tumor. A previous report regarding RARP with previous TUR-P showed that all were above pathological T2 [26]. This result may be because many more prostate tissues, including prostate cancer, were removed by HoLEP than by TUR-P. There has been much discussion about which patients with IPCa (cT1a or cT1b) should receive additional treatment [29][30][31]. A prospective study reported that younger age, PSA ≥ 0.2 ng/mL, and PSA ≥ 1.0 ng/mL after BPH surgery were predictive factors for invasive treatment of IPCa [32]. The percentage of residual tumors is likely to vary depending on the surgical procedure for BPH; therefore, consensus is still lacking on this issue.
Regarding oncological outcomes, a previous HoLEP was not a risk factor for biochemical recurrence after RARP. This  2 Kaplan-Meier curve of the biochemical recurrence-free rate after robot-assisted radical prostatectomy between the previous and no previous holmium laser enucleation of the prostate groups result is expected because the pathological T stage and Gleason grade were lower in the previous HoLEP group than in the no previous HoLEP group. In contrast, PSM and seminal vesicle invasion were independent risk factors for biochemical recurrence. Some previous studies have reported that PSM and seminal vesicle invasion were more likely to be associated with biochemical recurrences, which is consistent with ours [33][34][35]. This study has several limitations. First, the number of cases of RARP with a history of previous HoLEP was much lower than that of no previous RARP. Second, this study was retrospective, and the time interval between HoLEP and RARP was not consistent, which could be an important variable contributing to the degree of periprostatic inflammation and scarring over time in addition to influencing intraoperative outcomes. In addition, the evaluation of urinary continence was based solely on whether the number of pads used was less than one pad per day, and not on the American Urological Association Symptom Score, which is an international assessment of urinary continence. Therefore, it was difficult to determine whether there was a difference in urinary continence with or without previous HoLEP in a rigorous evaluation. However, studies on RARP after HoLEP have been reported from only one institution, and this is the first report from Asia to provide valuable insights for future studies.
In conclusion, the functional and oncological outcomes of RARP with previous HoLEP are comparable to those of RARP without previous HoLEP, and surgeons with adequate skills in RARP can safely perform it. In this era of robotic surgery, RARP is a treatment option for prostate cancer patients with a history of HoLEP.