The role of robot-assisted radical prostatectomy (RARP) for men with high-risk (HR) prostate cancer (PCa) has not been well studied.
To evaluate the indications for surgical treatment, technical aspects such as nerve sparing (NS) and lymph node dissection (LND), and perioperative outcomes of men with HR PCa treated with RARP.
A systematic expert review of the literature was performed in October 2012, searching the Medline, Web of Science, and Scopus databases. Studies with a precise HR definition, robotic focus, and reporting of perioperative and pathologic outcomes were included.
A total of 12 papers (1360 patients) evaluating RARP in HR PCa were retrieved. Most studies (67%) used the D’Amico classification for defining HR. Biopsy Gleason grade 8–10 was the most frequent HR identifier (61%). Length of follow-up ranged from 9.7 to 37.7 mo. Incidence of NS varied, although when performed did not appear to compromise oncologic outcomes. Extended LND (ELND) revealed positive nodes in up to a third of patients. The rate of symptomatic lymphocele after ELND was 3%. Overall mean operative time was 168 min, estimated blood loss was 189 ml, length of hospital stay was 3.2 d, and catheterization time was 7.8 d. The 12-mo continence rates using a no-pad definition ranged from 51% to 95% with potency recovery ranging from 52% to 60%. The rate of organ-confined disease was 35%, and the positive margin rate was 35%. Three-year biochemical recurrence–free survival ranged from 45% to 86%.
Although the use of RARP for HR PCa has been relatively limited, it appears safe and effective for select patients. Short-term results are similar to the literature on open radical prostatectomy. Variability exists for NS and the template of LND, although ELND improves staging and removes a higher number of metastatic nodes. Further study is required to assess long-term outcomes.
Keywords: Prostate cancer, Prostatectomy, High risk, Robotic, Lymph node dissection.
Prostate cancer (PCa), the most prevalent male malignancy in the United States, was diagnosed in approximately 240 000 men in 2012, and it represents the second most common cause of cancer-related death in the United States and Europe  . Despite prostate-specific antigen (PSA)-based screening and early detection guidelines, approximately 15–26% of PCa patients still present with high-risk (HR) features indicative of a more advanced and potentially lethal course  . HR characteristics are not only associated with biochemical recurrence but also with increased rates of secondary therapy, metastasis, and death  and .
Challenges exist in treating men with HR disease. The biologic behavior of HR cancer varies, and current diagnostic tools lack staging accuracy. Definitions of HR differ considerably, making prognostic assessment and outcome comparisons between treatments challenging  . Even for objective parameters such as Gleason score, grade migration can lead to time-dependent variance in risk groups  . Significant differences can exist within specific risk groups because patients may have anywhere from one to three HR features yet be classified similarly  .
Surgery and radiation are commonly offered to men with clinically localized PCa. Active surveillance leads to excellent long-term oncologic outcomes in low-risk patients, but HR patients appear to have the most to gain from definitive therapy  . Recent analyses advocating radical prostatectomy (RP) for men with HR cancer have demonstrated durable oncologic outcomes  . Nearly 40% of HR patients have organ-confined (OC) disease at RP, and these men experience excellent long-term survival while avoiding exposure to long-term androgen-deprivation therapy (ADT)  . Depending on the HR definition used, Yossepowitch et al. found OC cancers in 22–63% of patients undergoing RP with 72–98% metastasis-free survival 10 yr after surgery  . Despite the higher likelihood of biochemical recurrence and secondary therapy, HR patients have 10-yr cancer-specific survival (CSS) estimates after RP of approximately 90%  . European Association of Urology (EAU) guidelines now support a role for RP in select HR patients as a treatment option that may include a multimodality approach  .
Although RP is an important therapeutic option for select patients with HR PCa, the role of robot-assisted radical prostatectomy (RARP) has not been well investigated. No large series of RARP in HR patients or randomized trials comparing RARP with other treatments have been reported. In the past decade, RARP has been rapidly adopted into clinical practice, although only recently have outcomes specifically evaluated HR disease. Recent reviews comparing RARP with open RP have demonstrated similar positive surgical margin and biochemical recurrence rates with reduced blood loss and need for blood transfusion  as well as potential benefits to continence and erectile function recovery  . This review evaluates the indications, technical aspects, and short-term outcomes of RARP for men with HR clinically localized PCa.
2. Evidence acquisition
A systematic literature search of the Medline, Web of Science, and Scopus databases was performed in October 2012 using medical subject headings and free-text protocol. The search was restricted to the terms radical prostatectomy and lymph node dissection and publications written in the English language. In addition, the following limits were selected: male humans, cancer, and publications from January 1, 2000, to the present. American Urologic Association (AUA) and EAU abstracts were also reviewed, although they were excluded from the analysis. Review articles, abstracts, small case series, and publications not reporting categorical data for HR patients were excluded. Any additional studies cited in the references of the search papers were further reviewed.
Eligibility criteria for study inclusion consisted of (1) RARP surgical technique, (2) HR definition as well as selection of patients based on high PSA, Gleason grade 8–10, advanced clinical stage, or other HR criteria, and (3) reporting of perioperative and pathologic outcomes stratified for HR patients. Articles selected were reviewed and approved by all authors. Studies reporting outcomes based on clinical versus pathologic selection of HR patients were analyzed separately. Data extracted from the selected studies were entered into an electronic database. Complications were assessed according to established Martin criteria  and potency evaluation by the Mulhall criteria  . OC disease was defined as pathologic T2N0 disease on final specimen evaluation after RP. Descriptive statistics were used to summarize the clinical and pathologic data. Weighted averages were calculated because the number of patients varied across studies. The level of evidence for all studies was level 4 as described by the 2011 Oxford criteria  .
3. Evidence synthesis
Figure 1 depicts the systematic electronic search method. The search returned a total of 16 studies reporting RARP in HR PCa, 12 of which identified patients based on clinical criteria , , , , , , , , , , , and .
3.1. Definitions of high risk in robot-assisted radical prostatectomy series
Table 1 shows 12 RARP publications, all reported between 2008 and 2013, using a clinical definition of HR PCa. Of these, eight (67%) classified patients as HR using the D’Amico criteria (PSA >20 ng/ml, Gleason sum 8–10, clinical stage ≥T2c), and one study each by PSA, clinical stage, Gleason grade, and National Comprehensive Cancer Network (NCCN) (PSA >20 ng/ml, Gleason sum 8–10, clinical stage ≥T3) criteria alone. For the analyses by D’Amico criteria, 61% of patients met HR benchmarks by Gleason 8–10, which was significantly more common than clinical stage ≥T2c (10–36%) or PSA >20 ng/ml (16–23%).
|Study||Cases, n||High-risk criteria||PSA >20, n (%)||PSA, ng/ml, median/mean||≥cT2c, n (%)||cT3, n (%)||Gleason 8–10, n (%)|
|Shikanov et al. ||70||Gleason 8–10||–||8.36||4 (6)||0||70 (100)|
|Ham et al. ||121||≥cT3a||–||65.8||121 (100)||121 (100)||59 (49)|
|Zugor et al. ||147||PSA >20||147 (100)||34.8||–||–||–|
|Connolly et al. ||160||NCCN||48 (30)||9.9||38 (24)||32 (20)||120 (75)|
|Yee et al. ||62||D’Amico||–||6.9||–||19 (31)||46 (74)|
|Lavery et al. ||123||D’Amico||21 (17)||10.8||12 (10)||5 (4)||99 (81)|
|Rogers et al. ||69||D’Amico||11 (16)||7.2||25 (36)||12 (17)||43 (62)|
|Jayram et al. ||148||D’Amico||–||11.3||–||–||112 (76)|
|Sagalovich et al. ||82||D’Amico||–||7.4||–||–||76 (93)|
|Yuh et al. ||30||D’Amico||7 (23)||10.1||4 (13)||1 (3)||22 (73)|
|Ou et al. ||148||D’Amico||–||20.8||–||18 (13)||44 (30)|
|Jung et al. ||200||D’Amico||–|| Group 1: 8.7|
Group 2: 15.5
|–||119 (60)||80 (40)|
NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.
All studies were level 4 evidence.
A total of 1360 patients (range per study: 30–200) were examined. Length of follow-up after RARP ranged from 9.7 to 37.7 mo. Neoadjuvant ADT was administered in <5% of patients. Presenting clinical characteristics varied among studies even within the same selection criteria. For instance, median PSA was 12 ng/ml (range: 6.9–20.8 ng/ml) for the D’Amico selected studies but 65.8 ng/ml in a study of clinical T3 tumors  . Three studies reported percentage of positive biopsy cores ranging from 33% to 37%.
3.2. Technique of robot-assisted radical prostatectomy in high-risk prostate cancer
3.2.1. Nerve-sparing robot-assisted radical prostatectomy for high-risk prostate cancer
In the retrieved publications, NS was highly variable, ranging from 0% to 100% of patients  and , reflecting differences in tumor characteristics, patient population, or surgeon preference. Lavery et al. studied the performance of NS in HR patients and used visual cues to identify poorly defined planes, bulging of the capsule, or appearance of prostate tissue on the neurovascular bundle  . Intraoperative frozen section was also an option to guide NS. In this analysis, NS was performed in 73% of patients, excluding those with biopsy-proven seminal vesicle invasion, extracapsular extension on endorectal coil magnetic resonance imaging (MRI), or high-volume, high-grade disease. Controlling for pathologic disease characteristics, NS was not associated with a higher risk of positive surgical margins or biochemical recurrence. In a separate analysis, Casey et al. showed that NS, either bilateral or unilateral, was not associated with increased positive margins in patients with extraprostatic (pT3) disease  .
3.2.2. Lymph node dissection in high-risk prostate cancer
Despite staging and possible therapeutic benefits of lymph node dissection (LND), seven studies (58%) either did not specify the template of dissection or performed limited LND. Reasons for omitting or limiting LND were not stated. Only four RARP studies reported consistent use of extended lymph node dissection (ELND) in HR patients ( Table 2 ). The median lymph node yield from these studies was 18 nodes. Overall lymph node–positive rates ranged from 1% to 33% with the highest rates in the ELND cohorts. Figure 2 depicts a completed ELND during RARP. Of note, robotic ELND did appear to increase operative time with the three series of longest operative time routinely performing ELND , , and . Table 3 illustrates the complications by study, although reporting methods varied. The rate of symptomatic lymphocele in ELND series was 3% (range: 2.4–6.6%).
|Study||Cases, n||LN dissection template, %||% of patients with LN dissection||LN yield||LN positive rate, %||pT2, n||pT2, %||Positive margins, %|
|Shikanov et al. ||70||Unspecified||–||–||12.9||33||47.1||24.0|
|Ham et al. ||121||Extended||100%||18.6||24.0||21||17.4||48.8|
|Zugor et al. ||147||Unspecified||100%||–||17.1||47||32.0||33.3|
|Connolly et al. ||160||Limited||27%||–||14.8||63||39.9||38.0|
|Yee et al. ||62||Unspecified||–||–||–||–||–||22.6|
|Lavery et al. ||123||Unspecified||100%||–||2.4||52||42.3||31.0|
|Rogers et al. ||69||Unspecified||–||–||1.4||26||37.7||42.0|
|Jayram et al. ||148||Standard||100%||15||12.3||67||46.0||20.5|
|Sagalovich et al. ||82||Extended||100%||13||13.4||–||–||12.0|
|Yuh et al. ||30||Extended||100%||22||33.3||9||30.0||26.7|
|Ou et al. ||148||Unspecified||96%||9||14.2||10||6.8||53.3|
|Jung et al. ||200||Standard: 78/Extended: 23||100%||Standard: 15/Extended: 24||Overall: 9/Extended: 22||96||48.0||41.5|
LN = lymph node.
All studies were level 4 evidence.
|Cases, n||LN dissection template||Lymphocele, %||Ileus||Anastomotic leakage, %||Deep vein thrombosis, %||Rectal injury, %||Total, %||Martin criteria fulfilled|
|Ham et al. ||121||Extended||2.5||2.5||0.8||0.0||1.7||8.3||6|
|Zugor et al. ||147||Unspecified||–||–||–||–||–||14.2||8|
|Rogers et al. ||69||Unspecified||–||–||–||–||–||5.8||6|
|Jayram et al. ||148||Standard||–||–||–||–||–||4||6|
|Sagalovich et al. ||82||Extended||2.4||–||–||–||–||–||4|
|Yuh et al. ||30||Extended||6.6||3.3||10.0||3.3||0.0||30.0||7|
|Ou et al. ||148||Unspecified||–||–||–||–||–||7.4||6|
|Jung et al. ||200||Standard: 78%/Extended: 23%||3.0||–||–||–||–||–||5|
LN = lymph node.
All studies were level 4 evidence.
3.3. Perioperative outcomes of robot-assisted radical prostatectomy in high-risk prostate cancer
Table 4 summarizes the operative and postoperative outcomes of RARP. Mean operative time was 168 min, and estimated blood loss was 189 ml. Mean length of hospital stay and catheterization time were 3.2 and 7.8 d, respectively. The average rate of OC disease was 35% (range: 7–48%), and the positive margin rate was 35% (range: 12–53%). Overall complication rates ranged from 3% to 30%, although many series did not fulfill the Martin criteria for complication reporting, and thus events may be underreported.
|Study||Cases||Estimated blood loss, ml||Operative time, min||Hospital length of stay, d||Catheter time, d|
|Ham et al. ||121||432||214||5.8||12.9|
|Zugor et al. ||147||183||164||–||5.7|
|Lavery et al. ||123||84||147||1.6||–|
|Rogers et al. ||69||150||175||1||7|
|Jayram et al. ||148||150||–||1||6|
|Sagalovich et al. ||82||150||111||–||–|
|Yuh et al. ||30||200||186||1||–|
|Ou et al. ||148||100||150||3||8|
|Jung et al. ||200||250||190||4||–|
All studies were level 4 evidence.
In studies considering only one clinical variable for HR classification, Zugor et al. compared 147 men with PSA >20 ng/ml with their entire RARP experience. Patients with a high PSA were at a significantly higher risk for non-OC disease, lymph node positivity, and positive margins  . For men with Gleason 8–10 on prostate biopsy, lower PSA, lower percentage of positive biopsy cores, and lower biopsy core percentage were all predictive of OC disease. Interestingly, Gleason downgrading was seen in 61% of patients  . Ham et al. analyzed 121 men with locally advanced (≥cT3) PCa and did not find an increase in rate of complications, operative time, blood loss, or hospital stay compared with clinically localized patients  .
3.4. Functional outcomes: continence and potency
Table 5 and Table 6 summarize the functional results with regard to urinary continence and potency recovery, respectively. NS use, whether unilateral, bilateral, or none, potency definitions, and technique varied among studies, likely contributing to the heterogeneity in reported outcomes. The 12-mo continence rates using a 0–1 safety pad definition ranged from 78% to 95%. Continence with a strict no-pad definition ranged from 51% to 95%, although the study with 51% continence included only men >70 yr of age. Several studies reported statistically significant improvements in the AUA symptom score by 3 points after RARP  and .
|Study||Cases, n||Continence definition||Data source||Continence rate, %|
|6 mo||12 mo||18–36 mo|
|Yee et al. ||62||0–1 pads/d||Validated questionnaire||–||92 (84 with 0 pads)||–|
|Lavery et al. ||123||0–1 pads/d||Validated questionnaire||–||78||–|
|Rogers et al. ||69||0–1 pads/d||Validated questionnaire||–||–||82 (51 with 0 pads)|
|Jayram et al. ||148||0–1 pads/d||Unspecified||–||–||92|
|Ou et al. ||148||0 pads||Surgeon interview||91||95||–|
All studies were level 4 evidence.
|Study||Cases, n||Potency definition||Age, yr||Nerve sparing, %||Evaluation group (%)||Data source||Potency rate, %||Mulhall criteria fulfilled|
|12 mo||26 mo|
|Lavery et al. ||123||SHIM ≥16||–||73 (58 BNS; 15 UNS)||72 (59) (preoperatively potent)||Validated questionnaire||56||–||4|
|Rogers et al. ||69||ESI||73||Unclear||21 (30) (preoperatively potent)||Questionnaire||–||33||5|
|Jayram et al. ||148||SHIM ≥17||61||80 (29 BNS; 51 UNS)||100 (68) (preoperatively potent)||Validated questionnaire||52||–||5|
|Ou et al. ||148||ESI||66||20% (9 BNS; 11 UNS)||30 (20) (patients with BNS or UNS)||Surgeon interview||60||–||4|
ESI = erections sufficient for intercourse; SHIM = Sexual Health Inventory for Men; BNS = bilateral nerve sparing; UNS = unilateral nerve sparing.
All studies were level 4 evidence.
Erectile function recovery at 12 mo after RARP ranged from 52% to 60%, depending on definition. Potency was 52–56% in two studies that used the validated Sexual Health Inventory for Men questionnaire. One study reported potency rates of 33%, although this was in an older patient cohort  . For select HR patients who underwent bilateral NS, Ou et al. found potency rates of 71%  . Overall study adherence to the Mulhall criteria was low with only 4 to 5 criteria fulfilled of a possible recommended 11.
3.5. Short-term oncologic outcomes
Table 7 summarizes the rates of additional therapy and early biochemical outcomes according to length of follow-up. Secondary therapy (radiation therapy [RT], ADT, or both) was administered in 9–23% of patients and would be expected to increase with longer follow-up. However, these rates are consistent with open RP series with a 10-yr follow-up showing a 24–65% need for additional therapy  .
|Cases, n||Median follow-up, mo||Additional therapy (RT and/or ADT), %||Definition of biochemical recurrence||Recurrence rates, %||Time to recurrence, mo|
|Shikanov et al. ||70||9.7||–||PSA >0.1||1-yr BCRFS: 72||5.7|
|Zugor et al. ||147||19.6||–||PSA ≥0.2 after nadir or nadir not reached||Recurrence free at follow-up: 80||–|
|Connolly et al. ||160||26.2||PSA >0.2||2-yr BCRFS: 56; 3-yr BCRFS: 45||–|
|Lavery et al. ||123||12.5||–||PSA >0.2||Recurrence free at follow-up: 74||4.6|
|Rogers et al. ||69||37.7||13||PSA ≥0.2 with confirmation||1-yr BCRFS: 91; 3-yr BCRFS: 86||9.7|
|Jayram et al. ||148||18||23.3||–||–||–|
|Ou et al. ||148||26.7||–||PSA >0.2 with confirmation||Recurrence free at follow-up: 80||–|
|Jung et al. ||200||22||9.0||PSA ≥0.2 in consecutive tests||Recurrence free at follow-up: 75||–|
ADT = androgen-deprivation therapy; BCRFS = biochemical recurrence–free survival; PSA = prostate-specific antigen; RT = radiation therapy.
All studies were level 4 evidence.
With respect to early biochemical outcomes, Zugor et al. reported a biochemical recurrence–free survival (BCRFS) rate of 80% at 20 mo  . Biochemical recurrence occurred in 14–55% of patients with 3-yr BCRFS rates ranging from 45% to 86%  and . Mean time to recurrence after RARP ranged from 4.6 to 9.7 mo. Uberoi et al. found that PSA, PSA density, and percentage of positive biopsy cores predicted favorable pathology (OC disease with negative surgical margins)  . PSA, clinical stage, pathologic grade  as well as evidence of lymph node metastases  were found to be significant predictors of biochemical recurrence.
For men with HR PCa, RP represents an option for select patients, and early outcomes of RARP in our systematic review are encouraging. Pathologic outcomes are comparable with a series of 1366 open RP patients examined by Briganti et al., and perioperative and functional outcomes resemble those of RARP in patients without HR disease ( Table 8 ). Rates of secondary therapy and early biochemical recurrence appear similar to open RP. ELND can be performed robotically, and the probability of nodal disease detection increases with more extensive dissection. NS in well-selected patients does not appear to compromise surgical margins or biochemical survival.
|Briganti et al. ||Present analysis||Novara et al./Ficarra et al.  and |
|No. of patients||1366||1360||–|
|Surgical technique||Radical retropubic||Robotic||Robotic|
|Risk of disease||High risk||High risk||All|
|Positive surgical margins||45%||35%||–|
|Lymph node yield||10||18 (for ELND)||–|
|Lymph node positive rate,%||23||1–33||–|
|BCRFS, %||69 (5-yr estimate)||45–86 (3-yr estimate)||–|
|Estimated blood loss, ml||–||189||166|
|Operative time, min||–||168||152|
|Complication rates, %||–||3–30||3–26|
|Potency at 12 mo, %||–||52–60||54–90|
|Continence (0 pads at 12 mo), %||–||51–95||84|
BCRFS = biochemical recurrence–free survival; ELND = extended pelvic lymph node dissection.
HR PCa represents a wide spectrum of disease depending on the definition used, but generally it denotes men more inclined to experience cancer-related consequences such as progression and death. Prior to the initiation of PSA, patients were more likely to be classified as HR due to an abnormal rectal examination suggesting locally advanced disease  . In contrast, nearly 70% of HR patients are now classified as such because of Gleason grade  , similar to the 61% in this contemporary review. Currently, no single definition characterizes all men with HR PCa. Instead, clinical stage, Gleason score, and PSA all predict recurrence and progression following primary treatment as well as cancer-related death  . Risk group stratification clusters patients that share similar clinical characteristics. Yossepowitch et al. analyzed eight different definitions of HR and found varying rates of biochemical recurrence, need for secondary therapy, metastasis, and death; however, 10-yr PCa-specific mortality did not exceed 11% for any single definition  . Nguyen et al. examined six common definitions of HR comprising clinical stage, PSA, biopsy Gleason score, and combinations thereof showing 5-yr BCRFS of 36–58%. Despite considerable differences in patient characteristics, BCRFS did not vary significantly depending on the definition used  .
Definitive therapy of HR cancers, often requiring a multimodal approach, appears to provide the greatest long-term survival benefit in patients with ample life expectancy. RT with concomitant ADT has been favored in the treatment of HR PCa without strong comparative evidence due to concerns of functional side effects, high lymph node positive rates, or unresectable disease in HR patients undergoing prostatectomy. Nonetheless, surgical treatment offers a viable alternative to RT plus ADT (NCCN and EAU guidelines  ). Multiple retrospective series, controlling for all known variables and selection bias, have suggested superior long-term oncologic outcomes with RP versus RT-based approaches for men with clinically localized HR PCa. Tewari et al. demonstrated significantly lower risk of all-cause or PCa mortality with treatment of high-grade cancer favoring RP over RT  . Other population-based studies, adjusting for all measurable variables, have also shown that RP may confer a survival advantage in clinically localized PCa over RT or observation. Zelefsky et al. determined an increase in metastatic progression with RT compared with RP  . Cooperberg et al. demonstrated a higher risk of cancer-specific mortality with RT compared with RP  . These latter two studies have suggested the greatest comparative survival advantage for surgery over radiation is for patients with HR PCa.
One of the most important benefits of RP as compared with nonsurgical therapy is pathologic staging of the primary cancer as well as regional lymph nodes. Although preoperative risk group stratification and nomograms may identify patients with adverse features, studies have established that pathologic variables such as pathologic Gleason and stage more accurately predict who may benefit from additional therapy  . In favorable situations, pathologic downgrading and downstaging at RP may potentially spare patients from receiving adjuvant therapy. About a third of high-grade biopsy Gleason scores (8–10) are subsequently downgraded at RP, and 26–31% will have OC disease  . Moreover, several authors have observed significant differences in outcomes with Gleason grade 8 compared with grade 9 disease, reflecting variable disease biology  and . For example, Wambi et al. in an RARP series found 5-yr BCRFS rates of 47% for Gleason 8 and 21% for Gleason 9 disease  . Lymphadenectomy at the time of RP confers information about the level and extent of nodal involvement and may guide initiation of earlier adjuvant ADT. Multiple series suggest an approximately 10–20% 10-yr disease-free recurrence without adjuvant therapy following LND for men with lymph node metastases  .
A pelvic LND for PCa has diagnostic, prognostic, and possibly therapeutic intent. Multiple series have suggested the extent and quality of a pelvic LND is not dependent on a specific surgical technique; rather, nodal yield is far more dependent on surgeon intent rather than the technical approach (open, laparoscopic, or robotic)  . The specific template of dissection for ELND remains a topic of debate. The EAU recommends that if a LND is to be performed, it should be an ELND  . Higher nodal yield provides more accurate staging. Abdollah et al. determined that with the removal of 20 lymph nodes, about 90% of patients were properly staged  . Burkhard et al. revealed up to 58% of patients with nodal invasion had metastases in the internal iliac nodes  . Therefore, at minimum, the nodes overlying the external iliac and internal iliac vessels and obturator fossae should be removed for ELND ( Fig. 3 ). Recent interest in replicating the open standard of pelvic LND with the surgical robot has demonstrated increases in nodal yield and detection of positive lymph nodes compared with a more limited dissection  . Categorically, this improves staging and removes cancerous tissue that may lead to biochemical recurrence or metastatic disease. Robotic ELND can safely achieve lymph node yields of 16–24 nodes  and . Operative timing of LND has been described either initially  , after posterior dissection is completed  , or after the vesicourethral anastomosis is complete. Several studies have showed an improvement in survival with LND that may be secondary to the removal of micrometastatic disease  . In a study of men randomized to extended or standard LND, HR patients experienced improved 6-yr BCRFS with ELND (71% vs 51%)  . In a longitudinal series of 406 patients undergoing limited or extended LND, no significant difference in overall or major complication rates was demonstrated  . Large randomized trials of extended versus limited LND have not been performed, although complication or erectile function rates may be affected by more extensive dissection  . Longer follow-up will be needed to determine the therapeutic benefits of ELND.
Another potential benefit of RP for HR PCa is the possible posttreatment avoidance of additional therapy. Approximately half of men will require multimodal therapy, either delivered in an adjuvant or salvage manner. Yossepowitch et al. found that 35–76% of HR patients avoided secondary therapy altogether 10 yr after surgery  . Increased scrutiny of prolonged systemic hormone therapy has revealed many detrimental side effects including osteoporosis, decreased libido and erections, hot flashes, fracture risk, and potential cardiovascular morbidity  . Men receiving RT for HR PCa are 3.5 times more likely to receive ADT than patients treated with RP  . For HR disease, primary treatment with RP has a 70% chance of avoiding ADT  . Boorjian et al. showed an increased risk of all-cause mortality with RT plus ADT compared with RP, potentially attributable to ADT morbidity or inferior cancer control  . Even if men ultimately require salvage androgen deprivation for disease control after RP, they may delay time to the initiation of ADT. The median time from RP to salvage ADT in the previously mentioned study was 10.3 yr.
Another advantage of RP is the expectation and significance of a nondetectable PSA. After RP in completely excised patients, serum PSA should decline to a nondetectable level. The sensitivity of post-RP PSA provides a prompt assessment of disease cure and control, allowing early recognition of recurrent disease and delivery of salvage RT if necessary. PSA kinetics after primary RT are less predictable, which could delay the recognition of recurrence for years. In a large comparative analysis, median time to salvage therapy following RP was 13 mo versus 69 mo for RT  . Primary treatment with RP allows for salvage RT with curative intent in the setting of a promptly recognized local recurrence. Even in patients with poorly differentiated disease and positive margins, recurrence after RP can be effectively treated with salvage radiation that may prevent metastatic progression. Long-term overall survival and CSS in patients requiring multimodal therapy remains excellent.
Historically, clinicians performing RP for HR patients recommended wide resection on the side of the disease  due to concerns for positive surgical margins. With contemporary HR tumor characteristics trending toward more OC disease, selective NS during RARP appears technically attainable and oncologically safe. Preoperative endorectal coil MRI has not been shown to predict T3 disease consistently at RARP  . Overall, a combination of considerations such as digital examination, high-resolution MRI, baseline potency, and intraoperative findings should guide NS.
Younger (<59 yr), healthier patients with HR PCa are most likely to benefit from RP  . Curative treatment with RP is ideally suited for HR patients with OC disease. In a multi-institutional series of 1366 HR men, 37% had OC disease  , which is similar to the 35% rate in RARP from the present review. Despite this seemingly low rate, their entire cohort experienced excellent CSS of 91% at 10 yr after RP. Other reasons beyond stage migration that more HR patients may now present with OC disease are improvements in imaging and resultant patient selection.
The role of RARP for HR PCa will be better understood as larger series mature and longer follow-up is available. Regardless of treatment approach, improving cure rates for HR PCa depends on earlier recognition of men destined to have locally advanced disease and supporting randomized trials of novel neoadjuvant and adjuvant treatment strategies. RARP offers a minimally invasive option to primary treatment of HR PCa with early outcomes that appear similar to open RP.
There are several limitations to this review including study heterogeneity, generally short follow-up, and lack of individual patient data. Overall oncologic follow-up of patients is short in all studies; therefore definitive interpretation of survival data are not possible at this time. Although the summarized data appear comparable to open RP series, there are no side-by-side analyses. Certain data such as LND template are missing in several studies, although nodal counts may serve as a surrogate for extent of dissection. No consensus agreement regarding adjuvant therapy for HR patients treated with RP has been determined. Accordingly, rates of adjuvant and salvage RT or ADT varied that could have a downstream effect on survival outcomes. For the individual patient, assessment of disease may be most effective using established nomograms, although many were derived in the era of limited LND that understages HR patients.
RARP appears to be a safe and effective option for selected patients with HR PCa either alone or as the initial step in a multimodal treatment plan. Neurovascular bundle preservation is feasible in selected cases and may improve functional outcomes. Extended lymphadenectomy improves staging, increases detection of positive lymph nodes, and can be done safely and thoroughly robotically. Further longitudinal study is required to assess the long-term survival benefit of primary RARP in men with HR PCa.
Author contributions: Bertram Yuh had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Tewari, Menon, Eggener.
Acquisition of data: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Menon, Eggener.
Analysis and interpretation of data: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Tewari, Menon, Eggener.
Drafting of the manuscript: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Tewari, Menon, Eggener.
Critical revision of the manuscript for important intellectual content: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Tewari, Menon, Eggener.
Statistical analysis: Yuh, Novara, Zorn, Eggener.
Obtaining funding: None.
Administrative, technical, or material support: Yuh, Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Tewari, Menon, Eggener.
Supervision: Novara, Zorn, Wilson, Kimm, Touijer, Artibani, Heidenreich, Menon, Eggener.
Other (specify): None.
Financial disclosures: Bertram Yuh certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
-  M.M. Center, A. Jemal, J. Lortet-Tieulent, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61:1079-1092
-  Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR. CaPSURE. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE) [published correction appears in J Urol 2004;171:811]. J Urol 2003;170:S21–5; discussion S26–7.
-  J.R. Rider, F. Sandin, O. Andrén, P. Wiklund, J. Hugosson, P. Stattin. Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study. Eur Urol. 2013;63:88-96
-  O. Yossepowitch, S.E. Eggener, A.M. Serio, et al. Secondary therapy, metastatic progression, and cancer-specific mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy. Eur Urol. 2008;53:950-959
-  A.V. D’Amico, R. Whittington, S.B. Malkowicz, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974
-  A.B. Jani, P.A. Johnstone, S.L. Liauw, V.A. Master, O.W. Brawley. Age and grade trends in prostate cancer (1974–2003): a Surveillance, Epidemiology, and End Results Registry analysis. Am J Clin Oncol. 2008;31:375-378
-  O. Yossepowitch, J.A. Eastham. Radical prostatectomy for high-risk prostate cancer. World J Urol. 2008;26:219-224
-  F. Abdollah, M. Sun, J. Schmitges, et al. Survival benefit of radical prostatectomy in patients with localized prostate cancer: estimations of the number needed to treat according to tumor and patient characteristics. J Urol. 2012;188:73-83
-  G. Ploussard, A. Masson-Lecomte, J.B. Beauval, et al. Radical prostatectomy for high-risk prostate cancer defined by preoperative criteria: oncologic follow-up in national multicenter study in 813 patients and assessment of easy-to-use prognostic substratification. Urology. 2011;78:607-613
-  A. Briganti, S. Joniau, P. Gontero, et al. Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer. Eur Urol. 2012;61:584-592
-  S. Yamamoto, S. Kawakami, J. Yonese, et al. Long-term oncological outcome and risk stratification in men with high-risk prostate cancer treated with radical prostatectomy. Jpn J Clin Oncol. 2012;42:541-547
-  A. Heidenreich, J. Bellmunt, M. Bolla, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61-71
-  G. Novara, V. Ficarra, R.C. Rosen, et al. Systematic review and meta-analysis of perioperative outcomes and complications after robot-assisted radical prostatectomy. Eur Urol. 2012;62:431-452
-  V. Ficarra, G. Novara, T.E. Ahlering, et al. Systematic review and meta-analysis of studies reporting potency rates after robot-assisted radical prostatectomy. Eur Urol. 2012;62:418-430
-  R.C. Martin II, M.F. Brennan, D.P. Jaques. Quality of complication reporting in the surgical literature. Ann Surg. 2002;235:803-813
-  J.P. Mulhall. Defining and reporting erectile function outcomes after radical prostatectomy: challenges and misconceptions. J Urol. 2009;181:462-471
-  OCEBM levels of evidence system. Oxford Centre for Evidence-Based Medicine Web site. http://www.cebm.net/index.aspx?o=5653 .
-  S.A. Shikanov, A. Thong, O.N. Gofrit, et al. Robotic laparoscopic radical prostatectomy for biopsy Gleason 8 to 10: prediction of favorable pathologic outcome with preoperative parameters. J Endourol. 2008;22:1477-1481
-  W.S. Ham, S.Y. Park, K.H. Rha, W.T. Kim, Y.D. Choi. 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;19:329-332
-  V. Zugor, J.H. Witt, A. Heidenreich, D. Porres, A.P. Labanaris. Surgical and oncological outcomes in patients with preoperative PSA >20 ng/ml undergoing robot-assisted radical prostatectomy. Anticancer Res. 2012;32:2091-2095
-  S.S. Connolly, P.J. Cathcart, P. Gilmore, 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;109:752-759
-  D.S. Yee, N. Narula, M.B. Amin, D.W. Skarecky, T.E. Ahlering. Robot-assisted radical prostatectomy: current evaluation of surgical margins in clinically low-, intermediate-, and high-risk prostate cancer. J Endourol. 2009;23:1461-1465
-  H.J. Lavery, F. Nabizada-Pace, J.R. Carlucci, J.S. Brajtbord, D.B. Samadi. Nerve-sparing robotic prostatectomy in preoperatively high-risk patients is safe and efficacious. Urol Oncol. 2012;30:26-32
-  C.G. Rogers, J.D. Sammon, S. Sukumar, M. Diaz, J. Peabody, M. Menon. Robot assisted radical prostatectomy for elderly patients with high risk prostate cancer. Urol Oncol. 2013;31:193-197
-  G. Jayram, G.J. Decastro, M.C. Large, 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;25:455-457
-  D. Sagalovich, A. Calaway, A. Srivastava, P. Sooriakumaran, A.K. Tewari. 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
-  B.E. Yuh, N.H. Ruel, R. Mejia, C.M. Wilson, T.G. Wilson. Robotic extended pelvic lymphadenectomy for intermediate- and high-risk prostate cancer. Eur Urol. 2012;61:1004-1010
-  Y.C. Ou, C.K. Yang, J. Wang, et al. The trifecta outcome in 300 consecutive cases of robotic-assisted laparoscopic radical prostatectomy according to D’Amico risk criteria. Eur J Surg Oncol. 2013;39:107-113
-  J.H. Jung, J.W. Seo, M.S. Lim, 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;22:785-790
-  J.T. Casey, J.J. Meeks, K.A. Greco, S.D. Wu, R.B. Nadler. Outcomes of locally advanced (T3 or greater) prostate cancer in men undergoing robot-assisted laparoscopic prostatectomy. J Endourol. 2009;23:1519-1522
-  J. Uberoi, D. Brison, N. Patel, I.S. Sawczuk, R. Munver. Robot-assisted laparoscopic radical prostatectomy in patients with prostate cancer with high-risk features: predictors of favorable pathologic outcome. J Endourol. 2010;24:403-407
-  C.J. Kane, J.C. Presti Jr., C.L. Amling, W.J. Aronson, M.K. Terris, S.J. Freedland, SEARCH Database Study Group. Changing nature of high risk patients undergoing radical prostatectomy. J Urol. 2007;177:113-117
-  C.T. Nguyen, A.M. Reuther, A.J. Stephenson, E.A. Klein, J.S. Jones. The specific definition of high risk prostate cancer has minimal impact on biochemical relapse-free survival. J Urol. 2009;181:75-80
-  A. Tewari, G. Divine, P. Chang, et al. Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy—a propensity scoring approach [published correction appears in J Urol 2007;177:1958]. J Urol. 2007;177:911-915
-  M.J. Zelefsky, J.A. Eastham, A.M. Cronin, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol. 2010;28:1508-1513
-  M.R. Cooperberg, A.J. Vickers, J.M. Broering, P.R. Carroll. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer [published correction appears in Cancer 2011;117:2825]. Cancer. 2010;116:5226-5234
-  H. Van Poppel, S. Joniau. An analysis of radical prostatectomy in advanced stage and high-grade prostate cancer. Eur Urol. 2008;53:253-259
-  C.O. Wambi, S.A. Siddiqui, L.S. Krane, P.K. Agarwal, H.J. Stricker, J.O. Peabody. Early oncological outcomes of robot-assisted radical prostatectomy for high-grade prostate cancer. BJU Int. 2010;106:1739-1745
-  P. Bader, F.C. Burkhard, R. Markwalder, U.E. Studer. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure?. J Urol. 2003;169:849-854
-  J.L. Silberstein, A.J. Vickers, N.E. Power, et al. Pelvic lymph node dissection for patients with elevated risk of lymph node invasion during radical prostatectomy: comparison of open, laparoscopic and robot-assisted procedures. J Endourol. 2012;26:748-753
-  F. Abdollah, M. Sun, R. Thuret, et al. Lymph node count threshold for optimal pelvic lymph node staging in prostate cancer. Int J Urol. 2012;19:645-651
-  F.C. Burkhard, U.E. Studer. The role of lymphadenectomy in high risk prostate cancer. World J Urol. 2008;26:231-236
-  V. Pagliarulo, D. Hawes, F.H. Brands, et al. Detection of occult lymph node metastases in locally advanced node-negative prostate cancer. J Clin Oncol. 2006;24:2735-2742
-  J. Ji, H. Yuan, L. Wang, J. Hou. Is the impact of the extent of lymphadenectomy in radical prostatectomy related to the disease risk? A single center prospective study. J Surg Res. 2012;178:779-784
-  Yuh BE, Ruel NH, Mejia R, Novara G, Wilson TG. Standardized comparison of robot-assisted limited and extended pelvic lymphadenectomy for prostate cancer. BJU Int. In press. http://dx.doi.org/10.1111/j.1464-410X.2012.11788.x .
-  V. Pagliarulo, S. Bracarda, M.A. Eisenberger, et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;61:11-25
-  R. Miocinovic, R.K. Berglund, A.J. Stephenson, et al. Avoiding androgen deprivation therapy in men with high-risk prostate cancer: the role of radical prostatectomy as initial treatment. Urology. 2011;77:946-950
-  S.A. Boorjian, R.J. Karnes, R. Viterbo, et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer. 2011;117:2883-2891
-  J.S. Brajtbord, H.J. Lavery, F. Nabizada-Pace, P. Senaratne, D.B. Samadi. Endorectal magnetic resonance imaging has limited clinical ability to preoperatively predict pT3 prostate cancer. BJU Int. 2011;107:1419-1424
-  A. Briganti, M. Spahn, S. Joniau, et al. Impact of age and comorbidities on long-term survival of patients with high-risk prostate cancer treated with radical prostatectomy: a multi-institutional competing-risks analysis. Eur Urol. 2013;63:693-701
a City of Hope Cancer Center, Duarte, CA, USA
b University Hospital of Verona, Verona, Italy
c University of Aachen, Aachen, Germany
d Memorial Sloan-Kettering Cancer Center, New York, NY, USA
e Henry Ford Hospital, Detroit, MI, USA
f University of Padua, Padua, Italy
g Weill Cornell Medical College, New York, NY, USA
h University of Montreal Hospital Center, Montreal, Canada
i University of Chicago Medicine and Biological Sciences, Chicago, IL, USA
☆ Please visit www.eu-acme.org/europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.
© 2013 European Association of Urology, Published by Elsevier B.V.