E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7

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Platinum Priority – Review – Prostate CancerEditorial by Francesco Montorsi on pp. 928–930 of this issue

The Role of Robot-assisted Radical Prostatectomy and Pelvic

Lymph Node Dissection in the Management of High-risk Prostate

Cancer: A Systematic Review

Bertram Yuh a,*, Walter Artibani b, Axel Heidenreich c, Simon Kimm d, Mani Menon e,Giacomo Novara f, Ashutosh Tewari g, Karim Touijer d, Timothy Wilson a, Kevin C. Zorn h,Scott E. Eggener i

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

Article info

Article history:

Accepted May 8, 2013Published online ahead ofprint on May 18, 2013

Keywords:

Prostate cancer

Prostatectomy

High risk

Robotic

Lymph node dissection

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Abstract

Context: The role of robot-assisted radical prostatectomy (RARP) for men with high-risk(HR) prostate cancer (PCa) has not been well studied.Objective: To evaluate the indications for surgical treatment, technical aspects such asnerve sparing (NS) and lymph node dissection (LND), and perioperative outcomes ofmen with HR PCa treated with RARP.Evidence acquisition: A systematic expert review of the literature was performed inOctober 2012, searching the Medline, Web of Science, and Scopus databases. Studieswith a precise HR definition, robotic focus, and reporting of perioperative and pathologicoutcomes were included.Evidence synthesis: A total of 12 papers (1360 patients) evaluating RARP in HR PCa wereretrieved. Most studies (67%) used the D’Amico classification for defining HR. BiopsyGleason grade 8–10 was the most frequent HR identifier (61%). Length of follow-upranged from 9.7 to 37.7 mo. Incidence of NS varied, although when performed did notappear to compromise oncologic outcomes. Extended LND (ELND) revealed positivenodes in up to a third of patients. The rate of symptomatic lymphocele after ELND was3%. Overall mean operative time was 168 min, estimated blood loss was 189 ml, lengthof hospital stay was 3.2 d, and catheterization time was 7.8 d. The 12-mo continencerates using a no-pad definition ranged from 51% to 95% with potency recovery rangingfrom 52% to 60%. The rate of organ-confined disease was 35%, and the positive marginrate was 35%. Three-year biochemical recurrence–free survival ranged from 45% to 86%.Conclusions: Although the use of RARP for HR PCa has been relatively limited, it appearssafe and effective for select patients. Short-term results are similar to the literature onopen radical prostatectomy. Variability exists for NS and the template of LND, althoughELND improves staging and removes a higher number of metastatic nodes. Further studyis required to assess long-term outcomes.

sociation of Urology. Published by Elsevier B.V. All rights reserved.

then be attributed

automatically.

# 2013 European As

* Corresponding author. City of Hope National Cancer Center, Urologic Oncology,1500 E. Duarte Road, Duarte, CA 91010, USA. Tel. +1 626 256 4673; Fax: +1 626 301 8285.

oh.org (B. Yuh).

E-mail address: byuh@c

0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.eururo.2013.05.026

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7 919

1. Introduction

Prostate cancer (PCa), the most prevalent male malignan-

cy 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 [1]. 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 [2]. HR characteristics are not

only associated with biochemical recurrence but also with

increased rates of secondary therapy, metastasis, and

death [3,4].

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 [5].

Even for objective parameters such as Gleason score, grade

migration can lead to time-dependent variance in risk

groups [6]. Significant differences can exist within specific

risk groups because patients may have anywhere from one

to three HR features yet be classified similarly [7].

Surgery and radiation are commonly offered to men with

clinically localized PCa. Active surveillance leads to excel-

lent long-term oncologic outcomes in low-risk patients, but

HR patients appear to have the most to gain from definitive

therapy [8]. Recent analyses advocating radical prostatec-

tomy (RP) for men with HR cancer have demonstrated

durable oncologic outcomes [9]. 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)

[10]. 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

[4]. 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% [11]. 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 [12].

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 compar-

ing RARP with open RP have demonstrated similar positive

surgical margin and biochemical recurrence rates with

reduced blood loss and need for blood transfusion [13] as

well as potential benefits to continence and erectile

function recovery [14]. This review evaluates the indica-

tions, 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) report-

ing 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 [15]

and potency evaluation by the Mulhall criteria [16]. 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 [17].

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 [18–29].

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 Net-

work (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%).

A total of 1360 patients (range per study: 30–200)

were examined. Length of follow-up after RARP ranged

[(Fig._1)TD$FIG]

Fig. 1 – Systematic electronic search method.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7920

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 [19]. Three

studies reported percentage of positive biopsy cores

ranging from 33% to 37%.

Table 1 – Summary of high-risk robot-assisted radical prostatectomy s

Study Cases, n High-riskcriteria

PSA >20,n (%)

Shikanov et al. [18] 70 Gleason 8–10 –

Ham et al. [19] 121 �cT3a –

Zugor et al. [20] 147 PSA >20 147 (100)

Connolly et al. [21] 160 NCCN 48 (30)

Yee et al. [22] 62 D’Amico –

Lavery et al. [23] 123 D’Amico 21 (17)

Rogers et al. [24] 69 D’Amico 11 (16)

Jayram et al. [25] 148 D’Amico –

Sagalovich et al. [26] 82 D’Amico –

Yuh et al. [27] 30 D’Amico 7 (23)

Ou et al. [28] 148 D’Amico –

Jung et al. [29] 200 D’Amico –

NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antige

All studies were level 4 evidence.

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 [19,26], reflecting

differences in tumor characteristics, patient population, or

eries by clinical criteria

PSA, ng/ml,median/mean

�cT2c,n (%)

cT3,n (%)

Gleason 8–10,n (%)

8.36 4 (6) 0 70 (100)

65.8 121 (100) 121 (100) 59 (49)

34.8 – – –

9.9 38 (24) 32 (20) 120 (75)

6.9 – 19 (31) 46 (74)

10.8 12 (10) 5 (4) 99 (81)

7.2 25 (36) 12 (17) 43 (62)

11.3 – – 112 (76)

7.4 – – 76 (93)

10.1 4 (13) 1 (3) 22 (73)

20.8 – 18 (13) 44 (30)

Group 1: 8.7

Group 2: 15.5

– 119 (60) 80 (40)

n.

Table 2 – Summary of high-risk robot-assisted radical prostatectomy series: pathologic outcomes and lymph node dissection

Study Cases, n LN dissectiontemplate, %

% of patients withLN dissection

LN yield LN positiverate, %

pT2, n pT2, % Positivemargins, %

Shikanov et al. [18] 70 Unspecified – – 12.9 33 47.1 24.0

Ham et al. [19] 121 Extended 100% 18.6 24.0 21 17.4 48.8

Zugor et al. [20] 147 Unspecified 100% – 17.1 47 32.0 33.3

Connolly et al. [21] 160 Limited 27% – 14.8 63 39.9 38.0

Yee et al. [22] 62 Unspecified – – – – – 22.6

Lavery et al. [23] 123 Unspecified 100% – 2.4 52 42.3 31.0

Rogers et al. [24] 69 Unspecified – – 1.4 26 37.7 42.0

Jayram et al. [25] 148 Standard 100% 15 12.3 67 46.0 20.5

Sagalovich et al. [26] 82 Extended 100% 13 13.4 – – 12.0

Yuh et al. [27] 30 Extended 100% 22 33.3 9 30.0 26.7

Ou et al. [28] 148 Unspecified 96% 9 14.2 10 6.8 53.3

Jung et al. [29] 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.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7 921

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 [23]. Intra-

operative 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 inva-

sion, 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 [30].

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.

[(Fig._2)TD$FIG]

Fig. 2 – Intraoperative extended pelvic lymphadenectomy during robot-assisted radical prostatectomy. E = external iliac vessels; I = internal iliacvessels; O = obturator vessels and nerve; OU = obliterated umbilicalartery; U = ureter.

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

[19,27,29]. Table 3 illustrates the complications by study,

although reporting methods varied. The rate of symptom-

atic lymphocele in ELND series was 3% (range: 2.4–6.6%).

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.

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 [20].

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. Interest-

ingly, Gleason downgrading was seen in 61% of patients

[18]. 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 [19].

3.4. Functional outcomes: continence and potency

Tables 5 and 6 summarize the functional results with regard

to urinary continence and potency recovery, respectively.

NS use, whether unilateral, bilateral, or none, potency

Table 3 – Summary of high-risk robot-assisted radical prostatectomy (RARP) series: complications of RARP and pelvic lymphadenectomy

Cases, n LN dissectiontemplate

Lymphocele, % Ileus Anastomoticleakage, %

Deep veinthrombosis, %

Rectalinjury, %

Total, % Martin criteriafulfilled

Ham et al. [19] 121 Extended 2.5 2.5 0.8 0.0 1.7 8.3 6

Zugor et al. [20] 147 Unspecified – – – – – 14.2 8

Rogers et al. [24] 69 Unspecified – – – – – 5.8 6

Jayram et al. [25] 148 Standard – – – – – 4 6

Sagalovich et al. [26] 82 Extended 2.4 – – – – – 4

Yuh et al. [27] 30 Extended 6.6 3.3 10.0 3.3 0.0 30.0 7

Ou et al. [28] 148 Unspecified – – – – – 7.4 6

Jung et al. [29] 200 Standard: 78%/

Extended: 23%

3.0 – – – – – 5

LN = lymph node.

All studies were level 4 evidence.

Table 4 – Summary of high-risk robot-assisted radical prostatectomy series: perioperative outcomes

Study Cases Estimated blood loss, ml Operative time, min Hospital length of stay, d Catheter time, d

Ham et al. [19] 121 432 214 5.8 12.9

Zugor et al. [20] 147 183 164 – 5.7

Lavery et al. [23] 123 84 147 1.6 –

Rogers et al. [24] 69 150 175 1 7

Jayram et al. [25] 148 150 – 1 6

Sagalovich et al. [26] 82 150 111 – –

Yuh et al. [27] 30 200 186 1 –

Ou et al. [28] 148 100 150 3 8

Jung et al. [29] 200 250 190 4 –

All studies were level 4 evidence.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7922

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 [22,24].

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 [24]. For select HR patients who underwent bilateral

NS, Ou et al. found potency rates of 71% [28]. Overall study

adherence to the Mulhall criteria was low with only 4 to

5 criteria fulfilled of a possible recommended 11.

Table 5 – Summary of high-risk robot-assisted radical prostatectomy s

Study Cases, n Continence definition Data s

Yee et al. [22] 62 0–1 pads/d Validated qu

Lavery et al. [23] 123 0–1 pads/d Validated qu

Rogers et al. [24] 69 0–1 pads/d Validated qu

Jayram et al. [25] 148 0–1 pads/d Unspecified

Ou et al. [28] 148 0 pads Surgeon inte

All studies were level 4 evidence.

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 [4].

With respect to early biochemical outcomes, Zugor et al.

reported a biochemical recurrence–free survival (BCRFS)

rate of 80% at 20 mo [20]. Biochemical recurrence occurred

in 14–55% of patients with 3-yr BCRFS rates ranging from

45% to 86% [21,24]. 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

eries: continence outcomes

ource Continence rate, %

6 mo 12 mo 18–36 mo

estionnaire – 92 (84 with 0 pads) –

estionnaire – 78 –

estionnaire – – 82 (51 with 0 pads)

– – 92

rview 91 95 –

Table 6 – Summary of high-risk robot-assisted radical prostatectomy series: potency outcomes

Study Cases,n

Potencydefinition

Age,yr

Nervesparing, %

Evaluation group (%) Datasource

Potency rate, % Mulhall criteriafulfilled

12 mo 26 mo

Lavery et al. [23] 123 SHIM �16 – 73 (58 BNS;

15 UNS)

72 (59)

(preoperatively potent)

Validated

questionnaire

56 – 4

Rogers et al. [24] 69 ESI 73 Unclear 21 (30)

(preoperatively potent)

Questionnaire – 33 5

Jayram et al. [25] 148 SHIM �17 61 80 (29 BNS;

51 UNS)

100 (68)

(preoperatively potent)

Validated

questionnaire

52 – 5

Ou et al. [28] 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.

Table 7 – Summary of high-risk robot-assisted radical prostatectomy series: recurrence outcomes

Cases, n Medianfollow-up, mo

Additional therapy(RT and/or ADT), %

Definition of biochemicalrecurrence

Recurrence rates, % Time torecurrence, mo

Shikanov et al. [18] 70 9.7 – PSA >0.1 1-yr BCRFS: 72 5.7

Zugor et al. [20] 147 19.6 – PSA �0.2 after nadir or nadir

not reached

Recurrence free at follow-up: 80 –

Connolly et al. [21] 160 26.2 PSA >0.2 2-yr BCRFS: 56; 3-yr BCRFS: 45 –

Lavery et al. [23] 123 12.5 – PSA >0.2 Recurrence free at follow-up: 74 4.6

Rogers et al. [24] 69 37.7 13 PSA �0.2 with confirmation 1-yr BCRFS: 91; 3-yr BCRFS: 86 9.7

Jayram et al. [25] 148 18 23.3 – – –

Ou et al. [28] 148 26.7 – PSA >0.2 with confirmation Recurrence free at follow-up: 80 –

Jung et al. [29] 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.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7 923

margins) [31]. PSA, clinical stage, pathologic grade [21] as

well as evidence of lymph node metastases [29] were found

to be significant predictors of biochemical recurrence.

3.6. Discussion

For men with HR PCa, RP represents an option for select

patients, and early outcomes of RARP in our systematic

Table 8 – Comparison of perioperative and pathologic outcomes of rad

Briganti et al. [10]

No. of patients 1366

Surgical technique Radical retropubic

Risk of disease High risk

Positive surgical margins 45%

Pathologic stage,%

pT2 25

pT3a 35

pT3b 33

Lymph node yield 10

Lymph node positive rate,% 23

BCRFS, % 69 (5-yr estimate)

Estimated blood loss, ml –

Operative time, min –

Complication rates, % –

Potency at 12 mo, % –

Continence (0 pads at 12 mo), % –

BCRFS = biochemical recurrence–free survival; ELND = extended pelvic lymph no

review are encouraging. Pathologic outcomes are compara-

ble 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

ical prostatectomy by technique and risk of disease

Present analysis Novara et al./Ficarra et al. [13,14]

1360 –

Robotic Robotic

High risk All

35% –

35 –

35 –

19 –

18 (for ELND) –

1–33 –

45–86 (3-yr estimate) –

189 166

168 152

3–30 3–26

52–60 54–90

51–95 84

de dissection.

[(Fig._3)TD$FIG]

Fig. 3 – Template of dissection for extended pelvic lymphadenectomy.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7924

well-selected patients does not appear to compromise

surgical margins or biochemical survival.

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 [2].

In contrast, nearly 70% of HR patients are now classified as

such because of Gleason grade [32], 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 progres-

sion following primary treatment as well as cancer-related

death [5]. 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 [4].

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 [33].

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 [12]). 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 [34]. 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 [35]. Cooperberg et al. demonstrated a

higher risk of cancer-specific mortality with RT compared

with RP [36]. 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 [33]. 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 [37]. Moreover, several authors have observed

significant differences in outcomes with Gleason grade

8 compared with grade 9 disease, reflecting variable disease

biology [11,38]. 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 [38]. 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 [39].

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) [40]. 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 [12]. 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 [41]. Burkhard et al. revealed up to 58% of

patients with nodal invasion had metastases in the internal

iliac nodes [42]. 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

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7 925

compared with a more limited dissection [27]. Categorical-

ly, 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 [27,29]. Operative timing of LND has been

described either initially [29], after posterior dissection

is completed [27], 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 [43]. In a study of men randomized

to extended or standard LND, HR patients experienced

improved 6-yr BCRFS with ELND (71% vs 51%) [44]. In a

longitudinal series of 406 patients undergoing limited or

extended LND, no significant difference in overall or major

complication rates was demonstrated [45]. Large random-

ized trials of extended versus limited LND have not been

performed, although complication or erectile function rates

may be affected by more extensive dissection [26]. 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. Approxi-

mately 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 [4]. Increased

scrutiny of prolonged systemic hormone therapy has

revealed many detrimental side effects including osteopo-

rosis, decreased libido and erections, hot flashes, fracture

risk, and potential cardiovascular morbidity [46]. Men

receiving RT for HR PCa are 3.5 times more likely to receive

ADT than patients treated with RP [2]. For HR disease,

primary treatment with RP has a 70% chance of avoiding

ADT [47]. 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 [48]. 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 nonde-

tectable 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 [35]. 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 [7]

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 [49]. 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 [50]. 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 [19], 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 improve-

ments 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 strate-

gies. 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 deter-

mined. 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.

4. Conclusions

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.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7926

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.

References

[1] Center MM, Jemal A, Lortet-Tieulent J, et al. International variation

in prostate cancer incidence and mortality rates. Eur Urol 2012;

61:1079–92.

[2] Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR. CaPSURE. Time

trends in clinical risk stratification for prostate cancer: implica-

tions for outcomes (data from CaPSURE) [published correction

appears in J Urol 2004;171:811]. J Urol 2003;170:S21–5; discus-

sion S26–7.

[3] Rider JR, Sandin F, Andren O, Wiklund P, Hugosson J, Stattin P. 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.

[4] Yossepowitch O, Eggener SE, Serio AM, et al. Secondary therapy,

metastatic progression, and cancer-specific mortality in men with

clinically high-risk prostate cancer treated with radical prostatec-

tomy. Eur Urol 2008;53:950–9.

[5] D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical

outcome after radical prostatectomy, external beam radiation ther-

apy, or interstitial radiation therapy for clinically localized prostate

cancer. JAMA 1998;280:969–74.

[6] Jani AB, Johnstone PA, Liauw SL, Master VA, Brawley OW. Age and

grade trends in prostate cancer (1974–2003): a Surveillance, Epi-

demiology, and End Results Registry analysis. Am J Clin Oncol 2008;

31:375–8.

[7] Yossepowitch O, Eastham JA. Radical prostatectomy for high-risk

prostate cancer. World J Urol 2008;26:219–24.

[8] Abdollah F, Sun M, Schmitges J, et al. Survival benefit of radical

prostatectomy in patients with localized prostate cancer: estima-

tions of the number needed to treat according to tumor and patient

characteristics. J Urol 2012;188:73–83.

[9] Ploussard G, Masson-Lecomte A, Beauval JB, et al. Radical prosta-

tectomy 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 substrati-

fication. Urology 2011;78:607–13.

[10] Briganti A, Joniau S, Gontero P, et al. Identifying the best candidate

for radical prostatectomy among patients with high-risk prostate

cancer. Eur Urol 2012;61:584–92.

[11] Yamamoto S, Kawakami S, Yonese J, 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;

42:541–7.

[12] Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate

cancer. Part 1: screening, diagnosis, and treatment of clinically

localised disease. Eur Urol 2011;59:61–71.

[13] Novara G, Ficarra V, Rosen RC, et al. Systematic review and meta-

analysis of perioperative outcomes and complications after robot-

assisted radical prostatectomy. Eur Urol 2012;62:431–52.

[14] Ficarra V, Novara G, Ahlering TE, et al. Systematic review and meta-

analysis of studies reporting potency rates after robot-assisted

radical prostatectomy. Eur Urol 2012;62:418–30.

[15] Martin II RC, Brennan MF, Jaques DP. Quality of complication

reporting in the surgical literature. Ann Surg 2002;235:803–13.

[16] Mulhall JP. Defining and reporting erectile function outcomes after

radical prostatectomy: challenges and misconceptions. J Urol 2009;

181:462–71.

[17] OCEBM levels of evidence system. Oxford Centre for Evidence-

Based Medicine Web site. http://www.cebm.net/index.aspx?o=

5653.

[18] Shikanov SA, Thong A, Gofrit ON, 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.

[19] 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.

[20] Zugor V, Witt JH, Heidenreich A, Porres D, Labanaris AP. Surgical

and oncological outcomes in patients with preoperative PSA

>20 ng/ml undergoing robot-assisted radical prostatectomy.

Anticancer Res 2012;32:2091–5.

[21] Connolly SS, Cathcart PJ, Gilmore P, et al. Robotic radical prostatec-

tomy 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.

[22] Yee DS, Narula N, Amin MB, Skarecky DW, Ahlering TE. Robot-

assisted radical prostatectomy: current evaluation of surgical mar-

gins in clinically low-, intermediate-, and high-risk prostate cancer.

J Endourol 2009;23:1461–5.

[23] 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.

[24] Rogers CG, Sammon JD, Sukumar S, Diaz M, Peabody J, Menon M.

Robot assisted radical prostatectomy for elderly patients with high

risk prostate cancer. Urol Oncol 2013;31:193–7.

[25] Jayram G, Decastro GJ, Large MC, et al. Robotic radical prosta-

tectomy in patients with high-risk disease: a review of short-

term outcomes from a high-volume center. J Endourol 2011;25:

455–7.

[26] 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 pros-

tatectomy and its impact on functional outcomes. BJU Int 2013;

111:85–94.

E U R O P E A N U R O L O G Y 6 5 ( 2 0 1 4 ) 9 1 8 – 9 2 7 927

[27] 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.

[28] Ou YC, Yang CK, Wang J, et al. The trifecta outcome in 300 consecutive

cases of robotic-assisted laparoscopic radical prostatectomy accord-

ing to D’Amico risk criteria. Eur J Surg Oncol 2013;39:107–13.

[29] Jung JH, Seo JW, Lim MS, 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.

[30] 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.

[31] Uberoi J, Brison D, Patel N, Sawczuk IS, Munver R. Robot-assisted

laparoscopic radical prostatectomy in patients with prostate cancer

with high-risk features: predictors of favorable pathologic out-

come. J Endourol 2010;24:403–7.

[32] Kane CJ, Presti Jr JC, Amling CL, Aronson WJ, Terris MK, Freedland

SJ, SEARCH Database Study Group. Changing nature of high risk

patients undergoing radical prostatectomy. J Urol 2007;177:

113–7.

[33] Nguyen CT, Reuther AM, Stephenson AJ, Klein EA, Jones JS.

The specific definition of high risk prostate cancer has minimal

impact on biochemical relapse-free survival. J Urol 2009;181:

75–80.

[34] Tewari A, Divine G, Chang P, et al. Long-term survival in men with

high grade prostate cancer: a comparison between conservative

treatment, radiation therapy and radical prostatectomy—a propen-

sity scoring approach [published correction appears in J Urol

2007;177:1958]. J Urol 2007;177:911–5.

[35] Zelefsky MJ, Eastham JA, Cronin AM, 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;28:1508–13.

[36] Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative

risk-adjusted mortality outcomes after primary surgery, radiother-

apy, or androgen-deprivation therapy for localized prostate cancer

[published correction appears in Cancer 2011;117:2825]. Cancer

2010;116:5226–34.

[37] Van Poppel H, Joniau S. An analysis of radical prostatectomy in

advanced stage and high-grade prostate cancer. Eur Urol 2008;

53:253–9.

[38] Wambi CO, Siddiqui SA, Krane LS, Agarwal PK, Stricker HJ, Peabody

JO. Early oncological outcomes of robot-assisted radical prostatec-

tomy for high-grade prostate cancer. BJU Int 2010;106:1739–45.

[39] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progres-

sion and survival of patients with positive lymph nodes after radical

prostatectomy. Is there a chance of cure? J Urol 2003;169:849–54.

[40] Silberstein JL, Vickers AJ, Power NE, 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;26:748–53.

[41] Abdollah F, Sun M, Thuret R, et al. Lymph node count threshold for

optimal pelvic lymph node staging in prostate cancer. Int J Urol

2012;19:645–51.

[42] Burkhard FC, Studer UE. The role of lymphadenectomy in high risk

prostate cancer. World J Urol 2008;26:231–6.

[43] Pagliarulo V, Hawes D, Brands FH, et al. Detection of occult lymph

node metastases in locally advanced node-negative prostate can-

cer. J Clin Oncol 2006;24:2735–42.

[44] Ji J, Yuan H, Wang L, Hou J. 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;178:779–84.

[45] 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.

[46] Pagliarulo V, Bracarda S, Eisenberger MA, et al. Contemporary role

of androgen deprivation therapy for prostate cancer. Eur Urol 2012;

61:11–25.

[47] Miocinovic R, Berglund RK, Stephenson AJ, et al. Avoiding androgen

deprivation therapy in men with high-risk prostate cancer: the role

of radical prostatectomy as initial treatment. Urology 2011;77:

946–50.

[48] Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival

after radical prostatectomy versus external-beam radiotherapy

for patients with high-risk prostate cancer. Cancer 2011;117:

2883–91.

[49] 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.

[50] Briganti A, Spahn M, Joniau S, 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.