Robot-Assisted Radical Prostatectomy in Patients With Clinically High-Risk Prostate Cancer: Surgical Feasibility and Long-Term Functional and Oncologic Outcomes

Robot-assisted radical prostatectomy (RARP) is an acceptable procedure for localized prostate cancer. However, RARP has not been offered to patients with high-risk prostate cancer. We report long-term functional and oncologic outcomes of patients who underwent RARP for clinically high-risk prostate cancer and to assess the role of RARP in patients with high-risk prostate cancer. Methods This study included 90 patients with high-risk prostate cancer according to the D'Amico criteria who underwent RARP between January 2014 and December 2019. High risk was based on the presence of a clinical stage of ≥ T2c, a pretreatment prostate-specic antigen level > 20 ng/mL, or a biopsy Gleason score ≥ 8. Functional outcomes including postoperative continence and potency were assessed at 1, 3, 6, and 12 months after RARP. Oncologic outcomes comprised positive surgical margins (PSMs), biochemical recurrence (BCR), BCR-free survival, and clinical recurrence (CR)-free survival rates at 1 and 3 years.


Background
Prostate cancer is the most common non-cutaneous malignancy in males in the USA and the second leading cause of cancer-related deaths in males [1,2]. Following the implementation of early screening and prostate biopsy, most patients are diagnosed with organ-con ned prostate cancer, which is potentially curable [3]. In patients with localized prostate cancer, robot-assisted radical prostatectomy (RARP) has largely replaced open radical prostatectomy as the standard surgical treatment [4]. However, 20-30% of patients with prostate cancer at initial diagnosis harbor clinically high-risk disease with locally advanced pathology, de ned as D'Amico high-risk disease [5][6][7]. Due to the underlying aggressive pathology, patients with high-grade prostate cancer and a Gleason score 8-10 may subsequently experience disease recurrence, which may result in early metastasis with signi cant morbidity and eventual mortality; up to 85% of these patients die of prostate cancer within 10 years of diagnosis [8].
Therefore, optimal treatment approaches for high-risk prostate cancer remain controversial and there are currently no standard treatments. Many surgeons are reluctant to perform RARP in patients with clinically high-risk prostate cancer, given the relative novelty of the procedure [9]. Speci cally, worse oncologic and functional outcomes are anticipated after radical prostatectomy in patients with high-risk prostate cancer. Thus, these patients are usually offered radiotherapy in combination with hormonal therapy, which is however an incomplete therapeutic approach with signi cant side effects and no proven survival bene ts [10,11].
Recently, several studies have described reasonable oncologic outcomes and survival advantages with radical prostatectomy as rst-line therapy in patients with high-risk prostate cancer [12,13]. Thus, the European Urology Association guidelines state that radical prostatectomy can be offered as a rst-line therapy in patients with high-risk prostate cancer as part of multimodality treatment [14].
The objective of the present study was to evaluate long-term functional and oncologic outcomes at one and three years after surgery in patients with clinically high-risk prostate cancer who underwent primary RARP.

Methods
This study included a retrospective analysis of 90 patients who presented with D'Amico high-risk prostate cancer and treated with RARP by a single experienced surgeon (> 1000 RARPs) between January 2014 and December 2019. High-risk prostate cancer was de ned using the D'Amico classi cation based on a pretreatment prostate-speci c antigen (PSA) > 20 ng/mL, a biopsy Gleason score ≥ 8, or clinical stage ≥ cT2c [7]. All patient underwent preoperative multiparametric magnetic resonance imaging to determine the location and distribution of prostate cancer.
The study was approved by the Hallym University Sacred Heart Hospital Ethics Committee. Written informed consent was obtained from all patients. Data were collected in a customized database and analyzed. All methods were carried out in accordance with relevant guidelines and regulations. We assessed following demographic data: age, body mass index, American Society of Anesthesiologists score, prostate volume, PSA level, and biopsy Gleason score. Comorbidities were assessed using the ageadjusted Charlson comorbidity index scoring system [15]. Baseline sexual function before RARP was assessed using the Sexual Health Inventory for Men questionnaire (SHIM) questionnaire, and preoperative continence was evaluated using the International Prostate Symptom Score (IPSS). Postoperative complications were recorded and evaluated using the Clavien-Dindo classi cation [16].
Primary endpoint was postoperative long-term 1-3 years functional and oncologic outcomes after RARP. At 1, 3, 6, and 12 months after RARP, we evaluated potency rates using the SHIM questionnaire and continence rates using a daily pad-weighing test. Postoperative return of erectile function was scored as ≥ 4 on question 2 of the SHIM questionnaire or the ability to have successful sexual intercourse. Patients with zero pad use per day were considered. The following pathologic variables after RARP were also evaluated: pathologic stage, Gleason score, and positive surgical margins (PSMs). Oncologic outcomes comprised biochemical recurrence (BCR), BCR-free survival, and clinical recurrence (CR)-free survival rates at one and three years after RARP. According to American Urological Association guidelines, BCR was de ned as two consecutive PSA values ≥ 0.2 ng/mL [17]. CR was de ned as local recurrence and/or distant metastasis con rmed by histology and/or imaging. Salvage therapy was de ned as the implementation of radiotherapy or hormonal therapy > 6 months following RARP. Patients who underwent salvage therapy were categorized to have developed BCR. Adjuvant therapy was de ned as the implementation of radiotherapy or hormonal therapy within six months following RARP in the absence of BCR.
Continuous variables are reported as medians with interquartile ranges (IQRs) and categorical variables as percentages. Continence, potency, BCR-free survival, and CR-free survival after RARP were analyzed using the Kaplan-Meier method with the log-rank test. All statistical analyses were performed using SPSS Statistics for Windows version 26.0 (IBM, Armonk, NY, USA).

Results
The baseline demographic, clinical, and pathologic data of the 90 patients included in the study are summarized in Table 1. The median operative time was 185 (IQR, 140-250) minutes, the estimated blood loss was 200 (IQR, 150-450) mL, and no patient experienced intraoperative complications. Pelvic lymphadenopathy was present in 5 of the 90 patients (5.6%). The catheter was removed 1 week after surgery in all patients. The overall postoperative Clavien-Dindo grade I-II complication rate was 8.9%. Within the rst year after RARP, no patient developed Clavien-Dindo grade ≥ III complications such as lymphocele and urinary retention, which would require additional intervention. The continence rates were 54.4%, 68.9%, 77.8%, and 87.8% and the potency rates were 11.1%, 18.9%, 38.9%, and 56.7% at 1, 3, 6, and 12 months after RARP, respectively (Table 2). Figure 1 shows the Kaplan-Meier curve for continence recovery (a) and potency recovery (b). All patients received penile rehabilitation with regular use of oral phosphodiesterase type 5 inhibitors, starting one week after RARP until recovery of erectile function. The median time to continence and potency recovery was 2.3 (IQR, 0.5-12.5) and 6.5 (IQR, 3.2-15.5) months, respectively.  with radiotherapy and 7 patients (7.8%) with hormonal therapy > 6 months following RARP as well as 5 patients (5.6%) with secondary radiotherapy combination with hormonal therapy following adjuvant therapy. We summarize the details of postoperative therapies administered following RARP (Fig. 2).
The median follow-up duration was 51.

Discussion
For patients with clinically localized prostate cancer and a life expectancy beyond 10 years, radical prostatectomy is the treatment of choice. Recently, more than 80% of radical prostatectomy procedures in the USA are performed with robotic assistance [18]. Recent literature reviews and meta-analyses show that RARP is associated with decreased rates of PSMs, improvements in potency and continence recovery at short-term follow-up, and shorter hospital stay compared to open and laparoscopic radical prostatectomy approaches in low-and intermediate-risk patients [19].
However, 20-30% of patients continue to present with D'Amico high-risk prostate cancer at the time of initial diagnosis [5][6][7]. Optimal treatment for those diagnosed with high-risk prostate cancer is controversial, and the role of radical prostatectomy for locally advanced high-risk prostate cancer remains a topic of debate due to several reasons, including discouragement of surgical management and evasion of RARP because of inexperience with the technique and potential di culty in performing extended pelvic lymph node dissection [20]. Therefore, long-term oncologic outcomes of RARP in patients with high-risk prostate cancer remain poorly reported.
Several series have recently reported the role of RARP in patients with high-risk prostate cancer. Despite its aggressive behavior, the prognosis of high-risk prostate cancer is not uniformly poor. High-risk prostate cancer is con ned to the prostate in many patients, who may experience long-term progression-free survival after radical prostatectomy. Yossepowitch et al. analyzed radical prostatectomy outcomes in 957 patients with clinically localized high-risk prostate cancer and found that the cancer was con ned to the prostate in 43% of the patients [21]. Compared with low-and intermediate-risk patients, there was a 3.3fold increase in relapse hazard and higher likelihood of progression at ve and ten years after radical prostatectomy. A multicenter study by Sooriakumaran et al. concluded that radical prostatectomy for patients with resectable distant metastases was safe in expert hands in the setting of meticulous patient selection [22]. The adoption of radical prostatectomy as a treatment option for high-risk prostate cancer was based on the reported overall (and disease-speci c) survivals rates of 87% (93%), 70% (83%), and 58% (71%) at 5, 10, and 15 years, respectively [23].
The big question remains whether radical prostatectomy is superior to radiotherapy combined with hormonal therapy. Several studies retrospectively compared radical prostatectomy with radiotherapy. Boorijian et al. retrospectively compared outcomes between radical prostatectomy and radiotherapy combined with hormonal therapy in patients with high-risk prostate cancer and found comparable 10year cancer-free survival rates between the two groups; the authors also found that the risk of all-cause mortality was greater after radiotherapy with hormonal therapy compared to radical prostatectomy [24]. Zelefsky et al. found that cancer-free survival rates were comparable between radical prostatectomy and radiotherapy combined with hormonal therapy in patients with high-risk prostate cancer [25]. In that study, the absolute bene t of 7.8% in distant metastasis-free survival favored radical prostatectomy. Radical prostatectomy is therefore superior to radiotherapy combined with hormonal therapy in healthy patients with long life expectancy. Additionally, Boris et al. demonstrated the feasibility and durability of salvage RARP after failed radiotherapy and reported that the functional and oncologic outcomes of RARP were not inferior to those of open radical prostatectomy [26]. Based on these results, we suggest that, when feasible, RARP should be considered in patients with organ-con ned high-risk prostate cancer if the patient accepts the surgical risk. Salvage RARP is another good option for the treatment of patients with organ-con ned high-risk prostate cancer after failed radiotherapy.
In the present study, the median operative time was 185 minutes and the median intraoperative blood loss was 200 mL; only one patient with cardiovascular disease received intraoperative blood transfusion. These ndings are not substantially different than those reported in a systematic review of RARP outcomes in patients with high-risk prostate cancer [6]. The study reported that the mean operative time was 168 min, the estimated blood loss was 189 mL, the mean length of hospital stay was 3.2 days, and the duration of catheterization was 7.8 days. In the present study, the median duration of hospital stay and urinary catheter indwelling was seven days due to nature of the Korean medical insurance. Advantages of these long hospitalizations include the prevention of postoperative complications such as ileus and lymphocele.
The continence rates in the current study were consistent with the ndings of other study that demonstrated the bene ts of early recovery of urinary continence in patients with low-or intermediate-risk prostate cancer undergoing RARP, such as a report by Student et al. who found similar continence rates (62.5%, 68.8%, 75.0%, and 86.7% at 1, 2, 6, and 12 months, respectively) [27]. We performed the detrusorrhaphy technique which is designed for thickening and strengthening the detrusor muscles from the posterior bladder neck to the bilateral dissected pedicles area; this technique is thought to prevent hyper-mobilization of the bladder neck area, thereby reducing stress urinary incontinence, and is considered important for continence recovery as we previously reported [28]. Furthermore, using a validated sexual function questionnaire, we found that the rate of return baseline preoperative sexual function scores was 11.1% one month after RARP, which subsequently increased to 18.9%, 38.9%, and 56.7% at 3, 6, and 12 months after RARP, respectively. These outcomes are better than those reported by other studies using the same validated questionnaire in patients undergoing RARP. In their study examining nerve-sparing in salvage RARP, Bonet et al. reported that the 12-month potency rate was 25.6% in the good nerve-sparing group and that good nerve-sparing tended to be predictive of potency after salvage RARP [29]. In the current study, we performed athermal clipless intrafascial nerve-sparing technique if indicated; this technique might be associated with improved viable tissue preservation within the neurovascular bundles as we previously reported [28].
In the present study, the rate of patients with stage pT2 organ-con ned prostate cancer by postoperative pathologic assessment was 31.3%, similar to that reported in the systematic review of RARP-related outcomes by Yuh et al., who found that the average rate of organ-con ned disease was 35% (range, 7-48%) [ [30]. Our analyses revealing 3-year BCR-free and CR-free survival rates of 85.5% and 90.8%, respectively, are comparable to those reported in a study of patients with high-risk prostate cancer by Rogers et al. [31].
In patients with high-risk prostate cancer, RARP should be performed by skilled and experienced surgeons rather than beginners to reduce complications and to achieve optimal surgical results, given that radical prostatectomy is associated with high morbidity. A study by Punnen et al. provides further support for the effect of surgical experience on improved outcomes with RARP in patients with high-risk prostate cancer [32].
The limitations of the present study are the retrospective and noncomparative design of the study, which was performed by a single surgeon in a single institution, and the small sample size. While the present study was not a randomized trial, we believe that the biases associated with the study design were minimal, given that the surgeon has already performed more than 1000 RARPs between 2007 and 2020 and that the surgical methods in patients with high-risk prostate cancer are not challenging. Despite the ongoing follow-up of the study patients, our initial results suggest optimal functional and oncologic outcomes with RARP in patients with high-risk prostate cancer. Future studies should be conducted to include larger cohorts with longer follow-up periods to concomitantly compare the functional and oncologic outcomes of RARP with radiotherapy and/or hormonal therapy in patients with high-risk prostate cancer in a standardized fashion.

Conclusion
RARP conferred long-term cancer control in most patients with high-risk prostate cancer and was a safe and feasible minimally invasive surgical alternative to radiotherapy or hormonal therapy in select patients with D'Amico high-risk prostate cancer. These results demonstrating the optimal functional and oncologic outcomes of RARP should be validated to assure the reproducibility of measurements in prospective randomized-controlled studies. Treatment strati cation tree based on the data of 90 patients with high-risk prostate cancer undergoing RARP RARP robot-assisted radical prostatectomy, BCR biochemical recurrence