|INVITED RESEARCH HIGHLIGHT
|Year : 2015 | Volume
| Issue : 6 | Page : 908-915
Robotic radical prostatectomy in high-risk prostate cancer: current perspectives
Abdullah Erdem Canda1, Mevlana Derya Balbay2
1 Yildirim Beyazit University, School of Medicine, Ankara Ataturk Training and Research Hospital, Department of Urology, Ankara, Turkey
2 Memorial Sisli Hospital, Department of Urology, Istanbul, Turkey
|Date of Web Publication||19-May-2015|
Abdullah Erdem Canda
Yildirim Beyazit University, School of Medicine, Ankara Ataturk Training and Research Hospital, Department of Urology, Ankara
Source of Support: None, Conflict of Interest: None
Around 20%-30% of patients diagnosed with prostate cancer (PCa) still have high-risk PCa disease (HRPC) that requires aggressive treatment. Treatment of HRPC is controversial, and multimodality therapy combining surgery, radiation therapy, and androgen deprivation therapy have been suggested. There has been a trend toward performing radical prostatectomy (RP) in HRPC and currently, robot-assisted laparoscopic RP (RARP) has become the most common approach. Number of publications related to robotic surgery in HRPC is limited in the literature. Tissue and Tumor characteristics might be different in HRPC patients compared to low-risk group and increased surgical experience for RARP is needed. Due to the current literature, RARP seems to have similar oncologic outcomes including surgical margin positivity, biochemical recurrence and recurrence-free survival rates, additional cancer therapy needs and lymph node (LN) yields with similar complication rates compared to open surgery in HRPC. In addition, decreased blood loss, lower rates of blood transfusion and shorter duration of hospital stay seem to be the advantages of robotic surgery in this particular patient group. RARP in HRPC patients seems to be safe and technically feasible with good intermediate-term oncologic results, acceptable morbidities, excellent short-term surgical and pathological outcomes and satisfactory functional results.
|How to cite this article:|
Canda AE, Balbay MD. Robotic radical prostatectomy in high-risk prostate cancer: current perspectives. Asian J Androl 2015;17:908-15
∗This article is based on a presentation delivered on the International Prostate Forum at the Annual Meeting of the American Urological Association, Orlando, Fl, USA, May 18, 2014.
Prostate cancer (PCa) accounts for almost 30% of all newly diagnosed cancers in men in the United States and is the second most frequent cause of cancer death in men.  Due to serum prostate specific antigen (PSA) screening, there is an increase in the percent of patients diagnosed with localized PCa.  However, around 20%-30% of patients diagnosed with PCa still have high-risk, nonmetastatic disease. 
In 1998, D'Amico et al. first proposed a three-group risk stratification system to predict posttreatment biochemical failure following radical prostatectomy (RP) and external-beam radiotherapy.  This system classified nonmetastatic PCa into low-, intermediate- and high-risk PCa according to initial serum PSA, clinical T stage and biopsy Gleason score ([Table 1]). Low-risk PCa was defined as 1992 AJCC T1/T2a, and PSA ≤10 ng ml−1 , and Gleason score ≤6. Intermediate-risk PCa was defined as 1992 AJCC T2b, and/or PSA 10-20 ng ml−1 and/or Gleason 7 disease. High-risk PCa (HRPC) was classified as having any one of the following features including 1992 AJCC ≥T2c, PSA >20 ng ml−1 or Gleason 8-10 disease.  On the other hand, Loeb et al. defined HRPC using two definitions including: (i) 1992 TNM of cT2b and biopsy Gleason score 8-10, or PSA ≥15 ng ml−1 , and (ii) those with 1992 TNM of cT3. 
|Table 1: Classification of nonmetastatic PCa into risk groups by D'Amico et al. according to initial serum PSA, clinical T stage and biopsy Gleason score4 |
Click here to view
Aggressive treatment is required in HRPC otherwise this disease might progress and cause serious symptoms and complications and eventually patient death.  Although treatment of HRPC is controversial, radiation therapy, androgen deprivation therapy, surgery and most importantly multimodality therapy combining surgery and radiation have been suggested in various studies , meaning that RP could only cure a percentage of this patient group. ,, The outcomes of the Swedish Registry Study that has been very recently published suggested that surgery seems to be superior to radiation therapy and longer cancer-specific survival (CSS) was achieved in the surgery group in patients with HRPC as per a 15-year CSS data.  Therefore, there has been a trend toward performing RP in HRPC patients. 
Although open RP (ORP) is a well-established and standard surgical technique in the surgical management of patients with PCa, robotic approach has become the most common approach for PCa surgery in USA.  Many authors have published their outcomes related with robot-assisted laparoscopic RP (RARP) with promising results particularly in low- and intermediate-risk PCa patients with similar oncological and functional outcomes to open surgery suggesting the advantages of decreased blood loss, shorter duration of hospital stay, decreased postoperative analgesic requirement and earlier convalescence in the robotic surgery group. ,,, On the other hand, the number of publications related to the use of robotic surgery in HRPC is very limited in the literature. They mostly have limited numbers of patients and short follow-up periods. Herein, we summarized the literature on RARP and HRPC.
| Technique of Robot-Assisted Radical Prostatectomy|| |
We previously reported our technique of RARP using the da Vinci-S surgical system (Intuitive Surgical, Sunnyvale, CA, USA).  We use a transperitoneal approach and place a total of 5 abdominal ports We avoid using electrocautery particularly at the tip of the seminal vesicles (SVs) in order not to damage the neurovascular bundles (NVBs) and use nonabsorbable endoclips.
Bilateral extended pelvic lymph node dissection (ePLND) is performed in intermediate- or high-risk PCa patients and in those with an at least 5% risk of pelvic LN involvement by PCa according to Partin's tables. 
Overall, our positive surgical margin ((+) SM) rate was 20% (6.7% in pT2 and 32.4% in pT3 disease). Of the patients, 82.9% had urinary control at the 3-month follow-up. Regarding patients with preoperative International Index of Erectile Function (IIEF) scores ≥19 (mean: 47.6, n = 46), mean IIEF score was 45.3 (n = 11) at the 9-month follow-up. Regarding patients with preoperative IIEF scores of 13-18 (mean: 16.3, n = 6), mean IIEF score was 17.0 (n = 3) at the 9-month follow-up. 
Tewari et al. prospectively evaluated outcomes of radical retropubic and robotic RP procedures.  They concluded that robotic RP was safer, less bloody and required shorter duration of hospital stay and urethral catheterization. In addition, they stated that the oncological and functional results were favorable in the robotic RP group. 
| Important Surgical Technical Features in High-Risk Patients During Robot-Assisted Radical Prostatectomy|| |
We suggest gaining sufficient surgical experience in low-risk cases before proceeding to perform advanced high-risk cases because there is a risk of losing tissues of dissection in advanced cases, and anatomic variations might be present. In robotic surgery, because we do not have the tactile sensation, we need to see the anatomical details very well and also know the anatomy in detail. In addition, bulky disease and involvement of SVs and bladder neck by PCa could make dissection during RARP more difficult. 
It has been suggested that HRPC may be associated with firm SVs that might suggest tumor invasion and necessitates careful manipulation of the tissues in order to completely remove with negative SMs ((−) SMs).  Following opening the Denonvillier's fascia, meticulous dissection should be done between the plane of rectum and prostate. In advanced cases, characterization of this plane might be difficult due to the presence of extra-capsular disease and in patients with previous androgen deprivation therapy.  It is important to keep in mind that wide dissection and resection might lead to rectal injury particularly in patients with extra-capsular disease. On the other hand, dissecting as close as up to the apex between the plane of prostate and rectum following opening the Denonvillier's fascia significantly facilitates the procedure.
Another important area of dissection is the plane between the bladder neck and prostate base. Some authors suggested avoiding the natural tendency to advance toward the prostate and use a perpendicular place of dissection between the bladder neck and prostate base in order to prevent a (+) SM. In case of suspicion, intraoperative frozen section analysis could also be useful. ,
Tewari et al.  suggested that defining periprostatic fascial planes, color and tissue characteristics, presence of inflammatory changes and adhesions and determination of freely separating bloodless plane showing loose shiny areolar tissue as visual clues to decrease the risk of posterior-lateral (+) SMs.
Stroup and Kane suggested meticulous circumferential dissection of the prostate apex in order to avoid (+) SMs. 
In summary, tissue characteristics might be different in HRPC patients during RARP that needs increased surgical experience.
| Preservation of Neurovascular Bundles in High-Risk Patients During Robot-Assisted Radical Prostatectomy|| |
In our surgical approach, we perform interfascial or intrafascial NVB preservation on the nontumor bearing prostate side and non-NVB sparing wide excision of the tumor-bearing side in HRPC patients during performing RARP. Although the lack of tactile feedback related with robotic surgery is a concern, intraoperative tissue characteristics affect our decision and type of NVB sparing in this patient group. In the presence of adherent periprostatic tissue or extensive adhesions and inability to define periprostatic fascial planes that might suggest extra-capsular disease, we do not perform NVB-sparing. Likewise, other authors suggested considering extrafascial or modified nerve sparing approach with medial endopelvic fascia incision in an attempt to balance surgical oncologic control with functional outcomes. 
Lavery et al. reported the outcomes of 123 high-risk patients with preoperative HRPC diagnosis. Of the patients, bilateral, unilateral, and nonnerve-sparing was performed on 58%, 15%, and 27%, respectively.  Poorly defined planes, bulging of the capsule and appearance of prostatic tissue on the NVBs were suggested as possible risk factors for NVB involvement.  They concluded that nerve-sparing was not associated with higher rates of (+) SMs or biochemical recurrence (BCR). The "trifecta" of continence, potency, and freedom from recurrence was achieved in 23% in their series.  Shikanov et al. reported significantly lower (+) SM rates in the mid- and posterolateral (+) SM location in extrafascial NVB sparing group compared to interfascial NVB sparing group in their series.  In a series of 35 patients with pT3 PCa patients, Casey et al. reported that bilateral or unilateral NVB sparing was not associated with increased (+) SMs.  In a single surgeon series of 500 RARPs performed by Yee et al. for patients with palpable disease on rectal examination, the (+) SM rate was detected as 9.9% (7.7% in cT2 and 26.3% in cT3 disease) and none of the (+) SMs were detected along the NVB.  In other series, unilateral and bilateral NVB sparing procedures have been reported in 15%-60% and 18%-58% of cases, respectively in patients with HRPC who underwent RARP in the literature. ,,
Although some authors have suggested preserving NVBs in preoperatively potent patients with IIEF-5 score of ≥5,  it is our policy to preserve NVBs regardless of the preoperative IIEF-5 score whenever technically possible depending on the intraoperative findings and tissue characteristics that is expected to have an impact on the postoperative urinary continence, too.
In summary, preservation of NVBs might be possible and safe during performing RARP in HRPC patients, which depends on patient factors and tissue characteristics.
| Limits and Technique of Extended Pelvic Lymph Node Dissection During Robot-Assisted Radical Prostatectomy|| |
Currently, ePLND rather than standard pelvic LN dissection (sPLND) is recommended during RARP.  It has been reported that lymphatic drainage of the prostate is not limited to the obturator and external iliac LNs, and an ePLND including the internal iliac, external iliac and obturator LNs increases LN yield that is expected to improve detection of LN metastasis.  Performing ePLND during RARP was suggested to carry the advantages of diagnostic and therapeutic benefits in patients with intermediate- or high-risk PCa. ,
Borders of ePLND during RARP include:
- Lateral border: genitofemoral nerves, psoas muscles, and ureters
- Medial border: cut edge of the endopelvic fascia over the NVBs, internal iliac vessels
- Superior border: common iliac arter and vein and presacral area
- Inferior border: node of Cloquet, circumflex iliac vein.
In our technique, we initially identify the ureter on both sides in the pelvis, incise the peritoneum overlying it and dissect it until its crossing over common iliac artery. We perform ePLND after the completion of prostatectomy and before performing vesico-urethral anastomosis. We remove all the lymphatic tissue surrounding the major vessels and their tributaries. Before starting the ePLND procedure, we decrease the intra-abdominal carbon dioxide pressure to 10 mmHg in order to better identify and see particularly the veins. We use monopolar or bipolar coagulation in addition to polymer or metal endoclips for the ligation of small vessels and lymphatics.
In our experience with robot-assisted laparoscopic radical cystectomy for bladder cancer, we demonstrated that ePLND up to the inferior mesenteric artery could be efficiently performed with sufficient LN yields. , Therefore, we apply the same technique for performing ePLND when we perform ePLND is RARP for HRPC. Regarding RARP, obtaining a minimum of 20 LNs was suggested to be removed for ePLND. , On the other hand, LN yield has been suggested to depend on both surgeon and pathologist. , In addition, a wider anatomic dissection during ePLND was reported to lead to a greater total LN yield and a higher rate of LN metastases. ,,
Performing ePLND before the removal of the prostate might be another option that allows the surgeon to send LNs for intraoperative frozen section analysis. Montorsi stated that if metastases are found, reinspection of the area could be carried out in order to make sure if complete LN dissection has been obtained. 
| Role of Preoperative Prostate Magnetic Resonance Imaging|| |
Due to the European Society of Urogenital Radiology guidelines, recommended use of magnetic resonance imaging (MRI) in PCa consists of multi-parametric MRI (mp-MRI) that includes a combination of high-resolution T2-weighted images (T2WI), and at least two functional MRI techniques leading to better characterization than T2WI with only one functional technique.  Although T2WI MRI mainly assesses anatomy of the prostate, diffusion weighted imaging and MR spectroscopic imaging (MRSI) specify lesion characterization.  On the other hand, dynamic contrast enhanced MRI has a higher sensitivity in PCa detection.  It was reported that mp-MRI can be helpful in NVB sparing and continence sparing surgery and for detecting minimal extra-capsular disease.  In addition, MRSI with T2WI was suggested as very helpful in both excluding and detecting high-grade cancers of >0.5 cc in volume. ,
Criteria for extra-capsular extension include irregularity and NVB thickening; bulge, loss of capsule and the capsular enhancement; measurable extra-capsular disease; obliteration of the recto-prostatic angle. Expansion; low T2 signal intensity; filling in of the prostate-SV angle; enhancement and impeded diffusion are regarded as the criteria for SV infiltration.
Although endorectal coil MRI was regarded as the state-of-the-art for staging PCa, it also has the disadvantages of increased cost and patient acceptability,  Brajtbord et al. reported that it has limited clinical ability to preoperatively predict pT3 PCa at RARP. 
Evaluation of preoperative digital rectal examination findings, high-resolution MRI findings, intraoperative tissue findings and erectile function status of the patient were suggested to guide NVB sparing at RARP. 
| Role of Preoperative Prostate Biopsy|| |
Currently, systematic transrectal ultrasound (TRUS) guided prostate biopsy (TRUS-Bx) is frequently used for the diagnosis of PCa. However, this technique has been reported the following disadvantages including poor identification of PCa with TRUS, detection of low-risk disease that might be suitable for active monitoring, misclassification of PCa compared to postoperative whole-mount pathologic evaluation. ,, A recent study compared the diagnostic efficacy of the MRI pathway with TRUS-Bx and found out that mp-MRI/magnetic resonance (MR)-guided biopsy reduced the detection of low-risk PCa and reduced the number of men requiring biopsy while improving the overall rate of detection of intermediate/high-risk PCa. 
| Open Versus Robotic Radical Prostatectomy in High-Risk Prostate Cancer|| |
Increasing number of publications exist in the literature comparing the outcomes of open versus robotic RP in HRPC. All of these studies are retrospective and no prospective, randomized study exists currently. Patients with neoadjuvant anti-androgen or hormonal therapy were excluded in these studies. Although patient characteristics of the study groups were similar in these retrospective studies, an inevitable bias exists related to patient selection that could not be controlled. Another important point is that more than one surgeon was involved for the study groups that might also lead to lack of uniformity but also reflects more than one surgeon's experience.  Therefore, the results should be interpreted with caution, and strict conclusions should not be made at present.
Outcomes of selected published papers comparing open versus robotic RP in HRPC patients are summarized in [Table 2]. ,,, SM positivity, ,,,,, BCR , and biochemical recurrence-free survival (BCRFS) rates, , additional cancer therapy  and oncologic outcomes  were all reported to be similar in studies comparing open versus robotic RP in the surgical management of HRPC. Although the number of patients was limited, Smith et al. reported similar (+) SM rates in their open versus robotic RP series of HRPC patients (58% and 56.3%, respectively; P = 0.08). 
|Table 2: Outcomes of selected published papers comparing open versus robotic radical prostatectomy in HRPC patients |
Click here to view
Harty et al. included 153 and 152 patients in open and robotic RP groups, respectively in a retrospective study.  (+) SMs were detected in 15% and 12% of the patients with pT2 stage in open and robotic groups, respectively (P > 0.05). (+) SMs were detected in 74% and 79% of the patients with pT3 stage in open and robotic groups, respectively (P > 0.05). Pierorazio et al. included 743 and 105 patients in open and robotic RP groups, respectively in a retrospective study.  (+) SMs were detected in 5.7% and 8.3% of the patients with pT2 stage in open and robotic groups, respectively (P > 0.05).
Wambi et al. from the Vattikuti Urology Institute in USA evaluated the oncological outcomes of 368 patients with specimen Gleason 8 and 9 HRPC who underwent RARP. Mean overall BCRFS was 36% at 60 months. Regarding Gleason 8 and Gleason 9 PCa groups, BCRFS rates were reported as 47% and 21%, respectively (P < 0.001). In patients with extraprostatic extension (pT3a) with Gleason 8 and Gleason 9 PCa groups, BCRFS rates were detected as 52% and 21%, respectively at 5 years (P = 0.012). LN invasion, specimen Gleason score, pathological stage, and tumor volume were identified as predictors of BCRFS on multivariate analysis. 
Although LN dissection was performed in a similar way in both open versus robotic RP series, ,,, some authors such as Punnen et al. reported significantly lower LN yields thus reported lower LN metastasis rates in the RARP group.  While some authors reported similar LN yields,  some others reported inferior counts in the RARP groups. , In a systematic review by Yuh et al., it was stated that variability existed for the template of LN dissection, although ePLND improved staging and removed a higher number of metastatic nodes.  Silberstein et al.  stated that surgeons performing RARP were up to 5 times more prone to omit performing pelvic LN dissection compared to surgeons performing ORP even in HRPC patients due to the published literature. , Lower rates of LN dissections and LN yields in the RARP publications might be secondary to the learning curve of robotic surgeons and LN dissection policy of the institution. As an example, we perform ePLND in intermediate- or high-risk PCa patients and in those with an at least 5% risk of pelvic LN involvement by PCa according to Partin's tables.  On the other hand, Silberstein et al. performed ePLND in all of their patients with a 2% or greater risk of LN involvement assessed due to an established preoperative nomogram.  Particularly in low-risk PCa patients, ePLND was not performed in many RARP series due to these criteria on which debate is still ongoing.
Regarding complications, Gandaglia et al. reported similar complication rates between the two surgical treatment modalities.  As expected, less blood loss  and lower rates of blood transfusions  were reported in the RARP group compared to ORP in HRPC patients. Likewise, shorter duration of hospital stay was also detected in the RARP group. 
Rogers et al. evaluated the outcomes of RARP in a series of 69 elderly (≥70 years) patients.  Median duration of hospital stay was 1 day. Final pathologic examination revealed organ-confined disease with (−) SMs, and extra-capsular extension with (−) SMs were detected in 37.7% and 39.1% of the patients, respectively. There were only four complications (5.8%) which included urine leak and ileus in two patients each, respectively. At a median follow-up of 37.7 months, BCR occurred in 17.4% of the patients. Actuarial BCRFS was detected as 91% at 12 months and 86% at 36 months. At a median follow-up of 26.2 months, 81.5% of the patients was using no pad or 1 pad per day and 33.3% of the patients with preoperative SHIM score >21 achieved erections for sexual intercourse. Due to their experience, RARP in elderly patients with HRPC was regarded as a safe and feasible minimally invasive surgical procedure with good intermediate oncologic and functional outcomes. 
Technique and extent of NVB sparing were not mentioned clearly in most of the publications. Punnen et al. stated that complete bilateral NVB sparing was performed more often in the RARP group in their series.  Extent of NVB sparing might be expected to have an impact on the functional outcomes including urinary continence and erectile function. However, functional outcomes have not been reported in most of the literature comparing open versus robotic RP in HRPC patients, which needs further research.
In summary, RARP seems to have similar oncologic outcomes including (+) SM rates and LN yields with similar complication rates compared to open surgery in HRPC patients. In addition, decreased blood loss, lower rates of blood transfusion and shorter duration of hospital stay seem to be the advantages of robotic surgery in this patient group.
| Oncologic Outcomes Following Robot-Assisted Radical Prostatectomy at High-Risk Prostate Cancer Patients|| |
Lymph node yield, (+) lymph node rate and (+) surgical margin rates
In [Table 3], LN yield, (+) LN rates and (+) SM rates of selected HRPC series treated with RARP and ePLND are summarized. ,,,,,,, In the literature, not all of the published papers stated whether LN dissection was performed limited or extended in HRPC patient who underwent RARP. Therefore, we selected papers that stated ePLND was performed ([Table 3]). Due to this table, LN yield ranged between 6 and 24, (+) LN rate ranged between 3.8% and 33.3% and (+) SM rate ranged between 12.0% and 48.8%.
|Table 3: LN yield, (+) LN rate and (+) SM rate of selected HRPC series with stage pT2 disease treated with RARP and ePLND47 |
Click here to view
Yuh et al. from The City of Hope National Cancer Center in USA evaluated outcomes of 143 intermediate- and high-risk PCa patients whom they performed robotic ePLND following RARP.  Operative time for bilateral ePLND was between 30 and 45 min and median blood loss was 200 ml. No patient required blood transfusion. Average length of follow-up was 7 months in their series. Symptomatic lymphocele formation was detected in 3%, although routine pelvic imaging in the postoperative period was not performed. Therefore, the incidence of asymptomatic lymphocele might be higher in their series. They concluded that robotic ePLND can be performed safely with nodal yields >20. 
Liss et al. evaluated the outcomes and complications of patients who underwent sPLND and ePLND, or who did not undergo pelvic LN dissection (non-PLND) during RARP. When they examined ePLND (n = 41) and sPLND (n = 57) in only HRPC patients, mean LN yields were detected as 20 and 17, respectively (P = 0.048). In addition, (+) LN rates were detected as 29.3% and 12.3%, respectively (P = 0.042). Complication rates for all groups were similar. Lymphocele formation rates were 5% and 2.5%, respectively. They concluded that robotic ePLND improved LN yield and the proportion of LN metastases identified in HRPC patients. 
Jung et al. evaluated the outcomes of ePLND in HRPC patients.  They detected that 25% of (+) LNs were in the internal iliac and common iliac packets. In addition to the (+) internal iliac LNs, 75% of nodes were found in that location, exclusively. They concluded that ePLND including internal iliac packet should be performed during RARP in HRPC cancer that provided accurate pathologic staging and might have a survival benefit. 
Davis et al. from The University of Texas, MD Anderson Cancer Center, Houston stated that ePLND is feasible during RARP that increases LN yield and (+) LN rate particularly in HRPC patients. Due to their experience, median operative duration for ePLND was 42 min that was roughly double that of a sPLND. They suggested extensive clipping in order to avoid postoperative lymphoceles. 
Bmiochemical recurrence and recurrence-free survival
Silberstein et al. compared early oncologic outcomes of 961 ORP and 493 RARP patients.  Median follow-up for patients without BCR was 1-year and 0.7 year, respectively for ORP and RALP groups. In a multivariate analysis model adjusting for preoperative risk, no significant difference was detected in BCR rates between the groups. When National Comprehensive Cancer Network risk was used in place of nomogram risk, the results were similar. The 2-year probability of recurrence was 22.4% for HRPC patients in ORP group and was 15.2% in RARP group (P > 0.05). They concluded that open and robotic RP had similar early oncological outcomes in patients with HRPC. 
In a series of 233 HRPC patients, Punnen et al. reported recurrence-free survival at 2 years and 4 years as 79% and 66%, respectively after RARP.  Pierorazio et al. reported BRFS at 3 years as 67.8% in a series of 105 HRPC patients who underwent RARP.  In another study, mean 3-year recurrence-free survival was reported as 41.4% for 110 HRPC patients who underwent RARP and mean estimated 3-year overall survival was 95.4%.  In a series of 112 HRPC patients who underwent RARP, after a median follow-up of 13 months, Lavery et al. reported BCR in 20% of the patients. 
Presence of LN metastasis,  serum PSA level, clinical stage and pathologic grade  were detected to be associated with BCR following RARP in HRPC patients.
| Operative and Perioperative Parameters - Intraoperative Estimated Blood Loss, Operation Time and Duration of Hospital Stay|| |
In the published literature mean operative time ranged between 111 and 214 min; ,,,,,, mean estimated blood loss (EBL) ranged between 84 and 432 ml ,,,,,, and mean duration of hospital stay ranged between 1 and 5.8 days ,,,,,, in selected papers that evaluated RARP outcomes in HRPC patients.
The number of papers comparing operative and perioperative parameters including EBL, operation time and duration of hospital stay are very limited in the published literature. Punnen et al. reported significantly less EBL (200 vs 400 ml, P < 0.01) in the robotic group in a retrospective comparison of 177 ORP and 233 RARP in HRPC patients.  In another retrospective study, Gandaglia et al. reported significantly lower rates of blood transfusion and shorter duration of hospital stay in the robotic group when compared to open surgery in patients with HRPC. 
| Complications|| |
Gandaglia et al. evaluated if RARP was safe in HRPC patients.  They included 1512 patients with HRPC patients within the Surveillance, Epidemiology, and End Results Medicare-linked database diagnosed between 2008 and 2009. Overall, 706 (46.7%) and 806 (53.3%) patients underwent ORP and RARP, respectively. Following propensity-matched analyses, 706 patients remained. Due to their study, no differences were observed in complications between the two groups (30% and 28.3%, respectively in open vs robotic RP patients, P = 0.6). They stated that their finding persisted despite adjusting for tumor and patient characteristics in addition to hospital clustering. They also compared two groups for prediction of specific complication schemes that also showed no difference.
Other authors reported complication rates between 4% and 30% in HRPC patients who underwent RARP. ,,, Due to these studies, lymphocele, ileus, anastomotic leakage, deep vein thrombosis and rectal injury were among the reported complications. Ham et al. reported rectal injury rate as 1.7%.  Lymphocele formation was reported between 2.5% and 6.6% in other studies. , Although not all authors have reported their complication rates and type of complications in detail in the literature, due to the published series, RARP in HRPC patients seems to be a safe procedure with acceptable complication rates.
| Functional Outcomes - Urinary Continence and Erectile Function|| |
Functional outcomes following RARP include urinary continence and erectile function. In the published literature, only very few authors have reported their functional outcomes following RARP in HRPC patients. In a systematic review by Yuh et al., 1-year urinary continence (0-1 safety pad per day) rate ranged between 78% and 95% and erectile function recovery ranged between 52% and 60%.  Yee et al. reported their 1-year pad-free continence rate as 84% in HRPC patients who underwent RARP.  Preoperative erectile function status of the patient, postoperative adjuvant treatment requirement, NVB sparing (unilateral or bilateral), bladder neck preservation and urethral length should all be considered seriously in the evaluation of postoperative functional outcomes.
Rocco et al. suggested that restoration of the posterior aspect of the rhabdosphincter following ORP leads to substantial and significant reduction in time to early continence with no adverse effects.  Likewise, Rocco et al. confirmed same findings in a series of patients who underwent laparoscopic RP.  Others such as Simone et al. also reported outcomes supporting their outcomes.  However, due to the experience of Joshi et al.,  posterior reconstruction of the musculofascial complex was not found to improve early urinary incontinence after RARP. Ficarra et al. reported that recent systematic reviews of the literature showed only a minimal advantage in favor of posterior musculofascial reconstruction regarding urinary continence recovery.  They suggested performing posterior musculofascial reconstruction during RARP and described it as a simple, reproducible and safe surgical step that could be performed without significantly increasing operation time. In addition, they suggested that it might improve hemostasis and serve as a support for the urethra-vesical anastomosis. 
| Learning Curve and Surgeon's Experience|| |
No specific paper exists in the literature in terms of learning curve of RARP in HRPC patients. It was reported that outcomes of RP in open series were driven by experience of the surgeon. ,, Others also stated that increasing surgeon experience in addition to improvement of the surgical technique used decrease (+) SM rates in ORP. ,, Therefore, greater surgical volume and experience are expected to lead to better outcomes that might also apply to RARP in HRPC patients.
In conclusion, RARP seems to have similar oncologic outcomes including (+) SM rates, BCR rates, BCRFS rates, postoperative adjuvant therapy requirement rates and LN yields with similar complication rates compared to open surgery in HRPC. In addition, decreased blood loss, lower rates of blood transfusion and shorter duration of hospital stay seem to be the advantages of robotic surgery in this particular patient group. Tissue and tumor characteristics might be different in HRPC patients compared to low-risk group that needs increased surgical experience during performing RARP. RARP in HRPC patients seems to be safe and technically feasible with good intermediate-term oncologic results, acceptable morbidities, excellent short-term surgical and pathological outcomes and satisfactory functional results.
| Editorial Comment-(By Dr John W Davis, Department of Urology, The University of Texas, Md Anderson Cancer Center, Houston, Texas, USA)|| |
Prostate cancer is known to be one of the slowest growing solid tumors, and the lower end of grade and volume rarely threatens mortality during normal human longevity. Therefore, novel treatments for PCa can "look good" by selecting more favorable risk patients to treat. However, radical prostatectomy technique variations have one unique advantage - the full pathology report. Therefore, in the evolution of novel techniques in RP, the laparoscopic and now robot-assisted techniques can go through a reasonable learning curve in low-intermediate risk disease, but then move on to high-risk disease, which is likely the greater threat to the average patient diagnosed. Canda and Balbay review the literature with comments on the key techniques of robotic prostatectomy in high-risk disease with attention to key outcomes. At MD Anderson Cancer Center, approximately 15% of our high-risk patients taken for surgery are high-risk and are routinely performed with robot assistance - often with the involvement of a clinical trial of neoadjuvant therapy.
| Competing Interests|| |
All authors declare no competing financial interests.
| References|| |
Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al.
Cancer statistics, 2008. CA Cancer J Clin
2008; 58: 71-96.
Schröder FH. Prostate cancer around the world. An overview. Urol Oncol
2010; 28: 663-7.
Cooperberg MR, Cowan J, Broering JM, Carroll PR. High-risk prostate cancer in the United States, 1990-2007. World J Urol
2008; 26: 211-8.
D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, et al.
Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA
1998; 280: 969-74.
Loeb S, Smith ND, Roehl KA, Catalona WJ. Intermediate-term potency, continence, and survival outcomes of radical prostatectomy for clinically high-risk or locally advanced prostate cancer. Urology
2007; 69: 1170-5.
Thompson IM, Carroll PR, Carducci MA. Recommendations for defining and treating high risk localized prostate cancer. J Urol
2006; 176: S6-10.
Gonzalez JR, Laudano MA, McCann TR, McKiernan JM, Benson MC. A review of high-risk prostate cancer and the role of neo-adjuvant and adjuvant therapies. World J Urol
2008; 26: 475-80.
Lau WK, Bergstralh EJ, Blute ML, Slezak JM, Zincke H. Radical prostatectomy for pathological Gleason 8 or greater prostate cancer: influence of concomitant pathological variables. J Urol
2002; 167: 117-22.
Boorjian SA, Blute ML. Surgical management of high risk prostate cancer: the Mayo Clinic experience. Urol Oncol
2008; 26: 530-2.
Bahler CD, Foster RS, Bihrle R, Beck SD, Gardner TA, et al.
Radical prostatectomy as initial monotherapy for patients with pathologically confirmed high-grade prostate cancer. BJU Int
2010; 105: 1372-6.
Yossepowitch O, Eastham JA. Role of radical prostatectomy in the treatment of high-risk prostate cancer. Curr Urol Rep
2008; 9: 203-10.
Sooriakumaran P, Nyberg T, Akre O, Haendler L, Heus I, et al.
Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer: observational study of mortality outcomes. BMJ
2014; 348: g1502.
Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer
2010; 116: 5226-34.
Kawachi MH. Counterpoint: robot-assisted laparoscopic prostatectomy: perhaps the surgical gold standard for prostate cancer care. J Natl Compr Canc Netw
2007; 5: 689-92.
Ficarra V, Novara G, Artibani W, Cestari A, Galfano A, et al.
Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol
2009; 55: 1037-63.
Ficarra V, Novara G, Fracalanza S, D'Elia C, Secco S, et al.
A prospective, non-randomized trial comparing robot-assisted laparoscopic and retropubic radical prostatectomy in one European institution. BJU Int
2009; 104: 534-9.
Tewari A, Srivasatava A, Menon M, Members of the VIP Team. A prospective comparison of radical retropubic and robot-assisted prostatectomy: experience in one institution. BJU Int
2003; 92: 205-10.
Agarwal PK, Sammon J, Bhandari A, Dabaja A, Diaz M, et al.
Safety profile of robot-assisted radical prostatectomy: a standardized report of complications in 3317 patients. Eur Urol
2011; 59: 684-98.
Canda AE, Atmaca AF, Akbulut Z, Asil E, Kilic M, et al
. Results of robotic radical prostatectomy in the hands of surgeons without previous laparoscopic radical prostatectomy experience. Turk J Med Sci
2012; 42 Suppl 1: 1338-46.
Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, et al
. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology
2001; 58: 843-8.
Stroup SP, Kane CJ. Robotic-assisted laparoscopic prostatectomy for high-risk prostate cancer: technical considerations and review of the literature. ISRN Urol
2011; 2011: 201408.
Fromont G, Baumert H, Cathelineau X, Rozet F, Validire P, et al
. Intraoperative frozen section analysis during nerve sparing laparoscopic radical prostatectomy: feasibility study. J Urol
2003; 170: 1843-6.
Nakamura K, Kasraeian A, Anai S, Pendleton J, Rosser CJ. Positive surgical margins at radical prostatectomy: importance of intra-operative bladder neck frozen sections. Int Braz J Urol
2007; 33: 746-51.
Tewari AK, Patel ND, Leung RA, Yadav R, Vaughan ED, et al.
Visual cues as a surrogate for tactile feedback during robotic-assisted laparoscopic prostatectomy: posterolateral margin rates in 1340 consecutive patients. BJU Int
2010; 106: 528-36.
Lavery HJ, Nabizada-Pace F, Carlucci JR, Brajtbord JS, Samadi DB. Nerve-sparing robotic prostatectomy in preoperatively high-risk patients is safe and efficacious. Urol Oncol
2012; 30: 26-32.
Shikanov S, Woo J, Al-Ahmadie H, Katz MH, Zagaja GP, et al.
Extrafascial versus interfascial nerve-sparing technique for robotic-assisted laparoscopic prostatectomy: comparison of functional outcomes and positive surgical margins characteristics. Urology
2009; 74: 611-6.
Casey JT, Meeks JJ, Greco KA, Wu SD, Nadler RB. Outcomes of locally advanced (T3 or greater) prostate cancer in men undergoing robot-assisted laparoscopic prostatectomy. J Endourol
2009; 23: 1519-22.
Yee DS, Narula N, Amin MB, Skarecky DW, Ahlering TE. Robot-assisted radical prostatectomy: current evaluation of surgical margins in clinically low-, intermediate-, and high-risk prostate cancer. J Endourol
2009; 23: 1461-5.
Jayram G, Decastro GJ, Large MC, Razmaria A, Zagaja GP, et al.
Robotic radical prostatectomy in patients with high-risk disease: a review of short-term outcomes from a high-volume center. J Endourol
2011; 25: 455-7.
Shikanov SA, Thong A, Gofrit ON, Zagaja GP, Steinberg GD, et al.
Robotic laparoscopic radical prostatectomy for biopsy Gleason 8 to 10: prediction of favorable pathologic outcome with preoperative parameters. J Endourol
2008; 22: 1477-81.
Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, et al.
EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol
2011; 59: 61-71.
Abdollah F, Schmitges J, Sun M, Tian Z, Briganti A, et al.
A critical assessment of the value of lymph node dissection at radical prostatectomy: a population-based study. Prostate
2011; 71: 1587-94.
Schiavina R, Manferrari F, Garofalo M, Bertaccini A, Vagnoni V, et al.
The extent of pelvic lymph node dissection correlates with the biochemical recurrence rate in patients with intermediate- and high-risk prostate cancer. BJU Int
2011; 108: 1262-8.
Canda AE, Atmaca AF, Altinova S, Akbulut Z, Balbay MD. Robot-assisted nerve-sparing radical cystectomy with bilateral extended pelvic lymph node dissection (PLND) and intracorporeal urinary diversion for bladder cancer: initial experience in 27 cases. BJU Int
2012; 110: 434-44.
Akbulut Z, Canda AE, Ozcan MF, Atmaca AF, Ozdemir AT, et al
. Robot-assisted laparoscopic nerve-sparing radical cystoprostatectomy with bilateral extended lymph node dissection and intracorporeal studer pouch construction: outcomes of first 12 cases. J Endourol
2011; 25: 1469-79.
Novara G, Ficarra V, Rosen RC, Artibani W, Costello A, et al.
Systematic review and meta-analysis of perioperative outcomes and complications after robot-assisted radical prostatectomy. Eur Urol
2012; 62: 431-52.
Briganti A, Chun FK, Salonia A, Gallina A, Zanni G, et al.
Critical assessment of ideal nodal yield at pelvic lymphadenectomy to accurately diagnose prostate cancer nodal metastasis in patients undergoing radical retropubic prostatectomy. Urology
2007; 69: 147-51.
Briganti A, Capitanio U, Chun FK, Gallina A, Suardi N, et al.
Impact of surgical volume on the rate of lymph node metastases in patients undergoing radical prostatectomy and extended pelvic lymph node dissection for clinically localized prostate cancer. Eur Urol
2008; 54: 794-802.
Bochner BH, Herr HW, Reuter VE. Impact of separate versus en bloc pelvic lymph node dissection on the number of lymph nodes retrieved in cystectomy specimens. J Urol
2001; 166: 2295-6.
Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol
2002; 167: 1681-6.
Bader P, Burkhard FC, Markwalder R, Studer UE. Is a limited lymph node dissection an adequate staging procedure for prostate cancer? J Urol
2002; 168: 514-8.
Montorsi F. Robotic prostatectomy for high-risk prostate cancer: translating the evidence into lessons for clinical practice. Eur Urol
2014; 65: 928-30.
Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, et al.
ESUR prostate MR guidelines 2012. Eur Radiol
2012; 22: 746-57.
Villeirs GM, De Meerleer GO, De Visschere PJ, Fonteyne VH, Verbaeys AC, et al
. Combined magnetic resonance imaging and spectroscopy in the assessment of high grade prostate carcinoma in patients with elevated PSA: a single-institution experience of 356 patients. Eur J Radiol
2011; 77: 340-5.
Kumar R, Nayyar R, Kumar V, Gupta NP, Hemal AK, et al.
Potential of magnetic resonance spectroscopic imaging in predicting absence of prostate cancer in men with serum prostate-specific antigen between 4 and 10 ng/ml: a follow-up study. Urology
2008; 72: 859-63.
Brajtbord JS, Lavery HJ, Nabizada-Pace F, Senaratne P, Samadi DB. Endorectal magnetic resonance imaging has limited clinical ability to preoperatively predict pT3 prostate cancer. BJU Int
2011; 107: 1419-24.
Yuh B, Artibani W, Heidenreich A, Kimm S, Menon M, et al.
The role of robot-assisted radical prostatectomy and pelvic lymph node dissection in the management of high-risk prostate cancer: a systematic review. Eur Urol
2014; 65: 918-27.
Lecornet E, Ahmed HU, Hu Y, Moore CM, Nevoux P, et al.
The accuracy of different biopsy strategies for the detection of clinically important prostate cancer: a computer simulation. J Urol
2012; 188: 974-80.
Taira AV, Merrick GS, Bennett A, Andreini H, Taubenslag W, et al.
Transperineal template-guided mapping biopsy as a staging procedure to select patients best suited for active surveillance. Am J Clin Oncol
2013; 36: 116-20.
Pokorny MR, de Rooij M, Duncan E, Schröder FH, Parkinson R, et al
. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol
2014; 66: 22-9.
Harty NJ, Kozinn SI, Canes D, Sorcini A, Moinzadeh A. Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy. Int Braz J Urol
2013; 39: 639-46.
Pierorazio PM, Mullins JK, Eifler JB, Voth K, Hyams ES, et al.
Contemporaneous comparison of open vs minimally-invasive radical prostatectomy for high-risk prostate cancer. BJU Int
2013; 112: 751-7.
Punnen S, Meng MV, Cooperberg MR, Greene KL, Cowan JE, et al
. How does robot-assisted radical prostatectomy (RARP) compare with open surgery in men with high-risk prostate cancer? BJU Int
2013; 112: E314-20.
Busch J, Magheli A, Leva N, Hinz S, Ferrari M, et al.
Matched comparison of outcomes following open and minimally invasive radical prostatectomy for high-risk patients. World J Urol
2014; 32: 1411-6.
Silberstein JL, Su D, Glickman L, Kent M, Keren-Paz G, et al.
A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons. BJU Int
2013; 111: 206-12.
Gandaglia G, Abdollah F, Hu J, Kim S, Briganti A, et al.
Is robot-assisted radical prostatectomy safe in men with high-risk prostate cancer? Assessment of perioperative outcomes, positive surgical margins, and use of additional cancer treatments. J Endourol
2014; 28: 784-91.
Tai HC, Lai MK, Huang CY, Wang SM, Huang KH, et al.
Laparoscopic radical prostatectomy monotherapy, a more aggressive yet less invasive option, is oncologically effective in selected men with high-risk prostate cancer having only one D'Amico risk factor: experience from an Asian tertiary referral center. J Endourol
2014; 28: 165-71.
Smith JA Jr, Chan RC, Chang SS, Herrell SD, Clark PE, et al.
A comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical prostatectomy. J Urol
2007; 178: 2385-9.
Wambi CO, Siddiqui SA, Krane LS, Agarwal PK, Stricker HJ, et al
. Early oncological outcomes of robot-assisted radical prostatectomy for high-grade prostate cancer. BJU Int
2010; 106: 1739-45.
Patel VR, Sivaraman A, Coelho RF, Chauhan S, Palmer KJ, et al.
Pentafecta: a new concept for reporting outcomes of robot-assisted laparoscopic radical prostatectomy. Eur Urol
2011; 59: 702-7.
Feifer AH, Elkin EB, Lowrance WT, Denton B, Jacks L, et al
. Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Cancer
2011; 117: 3933-42.
Rogers CG, Sammon JD, Sukumar S, Diaz M, Peabody J, et al
. Robot assisted radical prostatectomy for elderly patients with high risk prostate cancer. Urol Oncol
2013; 31: 193-7.
Ham WS, Park SY, Rha KH, Kim WT, Choi YD. Robotic radical prostatectomy for patients with locally advanced prostate cancer is feasible: results of a single-institution study. J Laparoendosc Adv Surg Tech A
2009; 19: 329-32.
Sagalovich D, Calaway A, Srivastava A, Sooriakumaran P, Tewari AK. Assessment of required nodal yield in a high risk cohort undergoing extended pelvic lymphadenectomy in robotic-assisted radical prostatectomy and its impact on functional outcomes. BJU Int
2013; 111: 85-94.
Yuh BE, Ruel NH, Mejia R, Wilson CM, Wilson TG. Robotic extended pelvic lymphadenectomy for intermediate- and high-risk prostate cancer. Eur Urol
2012; 61: 1004-10.
Jung JH, Seo JW, Lim MS, Lee JW, Chung BH, et al.
Extended pelvic lymph node dissection including internal iliac packet should be performed during robot-assisted laparoscopic radical prostatectomy for high-risk prostate cancer. J Laparoendosc Adv Surg Tech A
2012; 22: 785-90.
Liss MA, Palazzi K, Stroup SP, Jabaji R, Raheem OA, et al
. Outcomes and complications of pelvic lymph node dissection during robotic-assisted radical prostatectomy. World J Urol
2013; 31: 481-8.
Davis JW, Shah JB, Achim M. Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs. BJU Int
2011; 108: 993-8.
Connolly SS, Cathcart PJ, Gilmore P, Kerger M, Crowe H, et al.
Robotic radical prostatectomy as the initial step in multimodal therapy for men with high-risk localised prostate cancer: initial experience of 160 men. BJU Int
2012; 109: 752-9.
Rocco F, Carmignani L, Acquati P, Gadda F, Dell'Orto P, et al.
Early continence recovery after open radical prostatectomy with restoration of the posterior aspect of the rhabdosphincter. Eur Urol
2007; 52: 376-83.
Rocco B, Gregori A, Stener S, Santoro L, Bozzola A, et al.
Posterior reconstruction of the rhabdosphincter allows a rapid recovery of continence after transperitoneal videolaparoscopic radical prostatectomy. Eur Urol
2007; 51: 996-1003.
Simone G, Papalia R, Ferriero M, Guaglianone S, Gallucci M. Laparoscopic "single knot-single running" suture vesico-urethral anastomosis with posterior musculofascial reconstruction. World J Urol
2012; 30: 651-7.
Joshi N, de Blok W, van Muilekom E, van der Poel H. Impact of posterior musculofascial reconstruction on early continence after robot-assisted laparoscopic radical prostatectomy: results of a prospective parallel group trial. Eur Urol
2010; 58: 84-9.
Ficarra V, Gan M, Borghesi M, Zattoni F, Mottrie A. Posterior muscolofascial reconstruction incorporated into urethrovescical anastomosis during robot-assisted radical prostatectomy. J Endourol
2012; 26: 1542-5.
Vickers A, Bianco F, Cronin A, Eastham J, Klein E, et al.
The learning curve for surgical margins after open radical prostatectomy: implications for margin status as an oncological end point. J Urol
2010; 183: 1360-5.
Swindle P, Eastham JA, Ohori M, Kattan MW, Wheeler T, et al.
Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol
2005; 174: 903-7.
Eastham JA, Kattan MW, Riedel E, Begg CB, Wheeler TM, et al.
Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens. J Urol
2003; 170: 2292-5.
Vickers AJ, Bianco FJ, Serio AM, Eastham JA, Schrag D, et al.
The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst
2007; 99: 1171-7.
[Table 1], [Table 2], [Table 3]
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