Contemporary role of salvage lymphadenectomy in patients with recurrence following radical prostatectomy

E U R O P E A N U R O L O G Y X X X ( 2 0 1 4 ) X X X – X X X

ava i lable at www.sciencedirect .com

journal homepage: www.europeanurology.com

EURURO-5594; No. of Pages 11

Platinum Priority – Collaborative Review – Prostate CancerEditorial by XXX on pp. x–y of this issue

Contemporary Role of Salvage Lymphadenectomy in Patients with

Recurrence Following Radical Prostatectomy

Firas Abdollah a,*, Alberto Briganti b, Francesco Montorsi b, Arnulf Stenzl c, Christian Stief d,Bertrand Tombal e, Hein Van Poppel f, Karim Touijer g

a Vattikuti Urology Institute and VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, MI, USA; b Department of Urology,

Vita-Salute University, San Raffaele, Milan, Italy; c Department of Urology, Eberhard-Karls-University Tuebingen, Tuebingen, Germany; d Department of

Urology, Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany; e Service d’Urologie, Cliniques universitaires Saint Luc, Universite

catholique de Louvain, Brussels, Belgium; f Department of Urology, Leuven Cancer Institute, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; g Urology

Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Article info

Article history:

Accepted March 17, 2014Published online ahead ofprint on March 26, 2014

Keywords:

Lymph node excision

Lymphatic metastasis

Neoplasm recurrence

local/surgery

Prostate-specific antigen/blood

Prostatectomy

Prostatic neoplasms/surgery

Salvage therapy

Treatment outcome

Abstract

Context: Prostate cancer (PCa) patients with isolated clinical lymph node (LN) relapse, limitedto the regional and/or retroperitoneal LNs, may represent a distinct group of patients who havea more favorable outcome than men with progression to the bone or to other visceral organs.Some data indirectly denote a beneficial impact of pelvic LN dissection on survival in thesepatients.Objective: To provide an overview of the currently available literature regarding salvage LNdissection (SLND) in PCa patients with clinical relapse limited to LNs after radical prostatec-tomy (RP).Evidence acquisition: A systematic literature search was conducted using the Medline,Embase, and Web of Science databases to identify original articles, review articles, andeditorials regarding SLND. Articles published between 2000 and 2012 were reviewed andselected with the consensus of all the authors.Evidence synthesis: Contemporary imaging techniques, such as 11C-choline positron emis-sion tomography and diffusion-weighted magnetic resonance imaging, appear to enhancethe accuracy in identifying LN relapse in patients with biochemical recurrence (BCR) andafter RP. In these individuals, SLND can be considered as a treatment option. The currentlyavailable data suggest that SLND can delay clinical progression and postpone hormonaltherapy in almost one-third of the patients, although the majority will have BCR. Anaccurate and attentive preoperative patient selection may help improve these outcomes.The most frequent complication after SLND was lymphorrhea (15.3%), followed by fever(14.5%) and ileus (11.2%). It is noteworthy that all examined cohorts originated fromretrospective single-institution series, with limited sample size and short follow-up.Consequently, the current findings cannot be generalized and warrant further investigationin future prospective trials.Conclusions: The current data suggest that SLND represents an option in patients with diseaserelapse limited to the LNs after RP; however, more robust data derived from well-designedclinical trials are needed to validate the role of SLND in this selected patient population.Patient summary: Salvage lymph node dissection (SLND) represents a treatment option in forpatients with prostate cancer relapse limited to the lymph nodes; however, more robust dataderived from well-designed clinical trials are needed to validate the role of SLND in thisselected patient population.

# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Vaand Evaluation, Henry FordE-mail address: firas.abdoll

Please cite this article in press as: Abdollah F, et al. Contemporary RFollowing Radical Prostatectomy. Eur Urol (2014), http://dx.doi.o

http://dx.doi.org/10.1016/j.eururo.2014.03.0190302-2838/# 2014 European Association of Urology. Published by Elsevier

ttikuti Urology Institute and VUI Center for Outcomes Research AnalyticsHospital, 2799 W. Grand Blvd., Detroit, MI 48202-2689, USA.

[email protected] (F. Abdollah).

ole of Salvage Lymphadenectomy in Patients with Recurrencerg/10.1016/j.eururo.2014.03.019

B.V. All rights reserved.

http://dx.doi.org/10.1016/j.eururo.2014.03.019

mailto:[email protected]



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1. Introduction

In contemporary surgically treated prostate cancer (PCa)

patients, the rate of biochemical recurrence (BCR) after

radical prostatectomy (RP) may reach 40% [1–4]. A

postoperative increase in prostate-specific antigen (PSA)

level is an index of tumor relapse, which could be localized

or systemic. Traditionally, salvage radiotherapy is offered to

patients with a suspected localized pelvic recurrence,

whereas hormonal therapy is offered to those with systemic

spread of the disease [5]. However, current advances in

clinical imaging techniques have allowed the identification

of a new group of patients with a unique relapse pattern.

These are patients with ‘‘systemic’’ disease progression,

which is limited to the regional and/or retroperitoneal

lymph nodes (LNs). These patients will be referred to as

patients with clinical LN relapse.

Patients with isolated clinical LN relapse may represent a

distinct group of patients who have a more favorable

outcome compared with men with progression to the bone

or to other visceral organs [6]. Recent reports found that

some of these patients may benefit from favorable cancer-

control outcomes when surgically treated [7,8]. This finding

is in line with previous retrospective data showing that

extended pelvic LN dissection (ePLND) could offer favorable

cancer control outcomes in PCa with LN invasion (LNI) at RP,

especially when the LNI volume is low (two or fewer

positive nodes) [9,10]. It is interesting to note that the

favorable impact of RP and ePLND held true even in patients

who did not receive adjuvant hormonal therapy after

surgery. Such data indirectly denote a beneficial impact of

pelvic LN dissection (PLND) on survival in these individuals.

However, it is not possible to directly apply these findings to

patients with post-RP clinical LN relapse, because the latter

represent a distinct clinical setting. Nevertheless, it may be

hypothesized that at least some patients with evidence of

limited clinical LN relapse after RP can benefit from salvage

LN dissection (SLND).

It is noteworthy that clinical LN relapse can be the

direct consequence of a suboptimal PLND at initial

treatment. Indeed, during the last two decades, the

majority of surgically treated PCa patients received either

a limited PLND (only obturator fossa) or no PLND at all

during initial treatment [11]. This finding was confirmed

in contemporary patients, in whom PLND was omitted in

28.5% and 18.2% of patients with respectively intermedi-

ate- and high-risk tumors treated with open RP, and in

49.5% and 32.7% of patients treated with robotic-assisted

RP, respectively [12]. These findings imply that even when

there are clear clinical indications, PLND is not always

performed. It appears that the introduction of laparo-

scopic and robot-assisted RP has significantly contributed

to the increased omission of PLND [12]. This situation may

translate to a higher proportion of patients with clinical

LN relapse in the coming years, which further points out

the necessity of working out an optimal treatment

strategy in these individuals. We reviewed the data

regarding the currently highly controversial procedure

of SLND in patients with clinical LN relapse after RP.


2. Evidence acquisition

We performed a literature search in December 2012 using

the Medline, Embase, and Web of Science databases. We

identified original articles, review articles, and editorials

addressing the role of SLND in PCa. Articles written in any

language other than English were excluded. The following

limits were used: humans; and gender (male). Keywords

included prostate cancer, salvage lymphadenectomy, salvage

lymph node dissection, and salvage lymph node excision. All

titles were screened, and studies were excluded if obviously

irrelevant. If there was any doubt concerning the eligibility

of a study, abstracts—and if necessary, the full text—were

examined. Additional references were identified from the

reference lists of these articles (Fig. 1). It is noteworthy that

all included articles consisted of case series, which

represent level 4 evidence.

To identify publications that address the evolution of

imaging techniques and their role in the management

of patients with PCa relapse, additional sources were

gathered by including the following keywords, arranged

in variable combinations: prostate cancer, positron emission

tomography (PET), computed tomography (CT), choline,

magnetic resonance imaging (MRI), diffusion-weighted MRI,

PSA, biochemical relapse, restaging, and recurrence.

3. Evidence synthesis

3.1. Diagnosis and staging of lymph node relapse after radical

prostatectomy

Cross-sectional imaging techniques, such as computed

tomography (CT) and magnetic resonance imaging (MRI),

have shown poor ability to detect LN metastasis

in patients with PCa [13] because a volumetric measure

(ie, LN diameter) was traditionally used to define LNI

status. This drawback limited the use of these imaging

techniques in the preoperative staging work-up. Howev-

er, in recent years, several developments and improve-

ments were introduced to the traditional imaging

techniques that escalated their performance as LN staging

procedures. In the current review, we focused on two

relatively novel imaging techniques that are increasingly

recognized as promising staging tools for clinical LN

relapse.

3.1.1. 11C-Choline positron emission tomography/computed

tomography scan

The theory beyond the use of the 11C-choline positron

emission tomography (PET)/CT scan is that tumor cells have

a higher turnover of essential cell membrane components,

such as phosphatidylcholine. After uptake by tumor cells,

radioactive choline is phosphorylated in high concentration

and built into the cell membrane, which allows its detection

by the PET scan. Since the introduction of 11C-choline

PET/CT, several reports have tried to evaluate its role as a

staging procedure in PCa patients with BCR after initial

radical treatment with curative intent [14–26]. These reports

showed a sensitivity that ranged between 38% and 98%. This



[(Fig._1)TD$FIG]

109 publica�ons iden�fied throughPubMed database search using the

following terms: prostate cancer,salvage lymphadenectomy, salvagelymph node dissec�on, and salvage

lymph node excision

Addi�onal 3 publica�ons were iden�fiedthrough search in the references of the 109

publica�ons

Poten�ally relevant 112 ar�cles or abstracts

45 ar�cles were excluded forduplicate

67 ar�cles were assessed for eligibility

60 ar�cles were excluded for:Dated before January 2000 (n = 16)Unrelated (n = 34)Case reports/review/comments (n = 5)Non-English (n = 5)

7 ar�cles were included in the systema�c review

Elegibility

Includ

edScreen

ing

Iden

�fica�o

n

----

Fig. 1 – The review process.

E U R O P E A N U R O L O G Y X X X ( 2 0 1 4 ) X X X – X X X 3


wide range might be mainly attributed to the heterogeneity

of the examined cohorts.

For the purpose of this review, we concentrated mainly

on reports that verified PET/CT accuracy using histologic,

biopsy, and/or follow-up data as the gold standard test

(Table 1). Some of these reports evaluated the performance

of 11C-choline PET/CT in detecting any clinical recurrence

(not specific to clinical LN relapse) in patients with BCR after

initial treatment with curative intent [15,18,24,27]. They

reported a sensitivity, specificity, positive predictive value

(PPV), negative predictive value (NPV), and predictive

accuracy of 73–95%, 40–93%, 86–92%, 61–87%, and 84–90%,

respectively. These data indicate that 11C-choline PET/CT

can be considered accurate enough in detecting nodal

recurrence in general.

However, only a few reports focused on the specific

correlation between PET/CT scan imaging and clinical LN

relapse at pathologic examination in patients who under-

went pelvic and/or retroperitoneal LN dissection (LND)

[19,28]. Scattoni et al. [19] prospectively evaluated the

performance of 11C-choline PET/CT scan in 25 patients with

BCR after RP who had no clinical recurrence. These authors

found that 11C-choline PET/CT scan sensitivity, specificity,


PPV, NPV, and accuracy were 64%, 90%, 86%, 72%, and 77%,

respectively [19]. After this initial report, several other

investigators explored the utility of 11C-choline PET/CT

scan. For example, Schilling et al. [28] analyzed the results

of 10 patients with BCR after either external-beam radiation

therapy or radical retropubic prostatectomy who under-

went laparoscopic lymphadenectomy for suspicious nodes

detected on 11C-choline PET/CT scan. These authors found

that only 7 of 10 patients included in the study had positive

LNs at pathologic examination. Therefore, they concluded

that 11C-choline PET/CT scan has a limited PPV in detecting

clinical LN relapse of PCa [28]. However, most of the

patients in this report received a suboptimal LND, as

evidenced by the low number of LNs removed (mean:

7.1 nodes). This finding could have biased the results and

led to an artificial underperformance of SLND. Indeed,

several reports documented a direct relationship between

the number of LNs removed and the LNI detection rate

[11,29–31]. The study by Scattoni et al. [19] examined a

bigger cohort of patients who were treated with an extended

SLND (mean: 21.9 nodes) and is therefore more reliable.

In another, smaller report, Winter et al. [32] investigated

the data on six patients with BCR after RP who were treated



Table 1 – Performance characteristics of positron emission tomography/computed tomography and magnetic resonance imaging in detecting prostate cancer nodal invasion and/or relapse

Study Patients, no. Nature of patients Site of tumor Imaging type Sensitivity, % Specificity, % Accuracy, %

De Jong et al. [14] 22 Relapse after initial treatment All sites 11C-Choline PET/CT scan 100 83.3 90.9

Picchio et al. [17] 100 Relapse after initial treatment All sites 11C-Choline PET/CT scan 80.0 93.3 86.0

Scattoni et al. [19] 25 Relapse after initial treatment Lymph nodes 11C-Choline PET/CT scan 100 66.6 92.0

Vees et al. [54] 11 Relapse after initial treatment Local recurrence 18F-Choline and/or 11C-acetate

PET/CT scan

43.0 50 45

Rinnab et al. [36] 50 Relapse after initial treatment All sites 11C-Choline PET/CT scan 94.8 36.3 82.0

Reske et al. [24] 49 Relapse after initial treatment Local recurrence 11C-Choline PET/CT scan 69.9 66.6 69.4

Husarik et al. [23] 68 Relapse after initial treatment All sites 18F-Choline PET/CT scan 90.0 100 91.1

Husarik et al. [23] 23 Relapse after initial treatment Lymph nodes 18F-Choline PET/CT scan 100 0 78.0

Schilling et al. [28] 10 Relapse after initial treatment Lymph nodes 11C-Choline PET/CT scan 100 0 70.0

Pelosi et al. [55] 56 Relapse after initial treatment All sites 18F-Choline PET/CT scan 82.7 96.2 89.2

Rinnab et al. [18] 15 Relapse after initial treatment Lymph nodes 11C-Choline PET/CT scan 100 0 60

Richter et al. [56] 73 Relapse after initial treatment All sites 2-Deoxy-2-[F-18]fluoro-D- glucose and

11C-choline PET/CT scan

61 100 62

Giovacchini et al. [50] 358 Relapse after initial treatment All sites 11C-Choline PET/CT scan 85.0 93.0 89.0

Panebianco et al. [57] 84 Relapse after initial treatment Local recurrence 18F-Choline PET/CT scan 83.0 63.0 81.0

Giovacchini et al. [58] 170 Relapse after initial treatment All sites 11C-Choline PET/CT scan 86.7 89.5 88.2

Bertagna et al. [20] 45 Relapse after initial treatment Local recurrence 11C-Choline PET/CT scan 60.0 91.0 84.0

Castellucci et al. [59] 102 Relapse after initial treatment All sites 11C-Choline PET/CT scan 83.0 100 94.0

Henniger et al. [60] 35 Relapse after initial treatment All sites 18F-Choline PET/CT scan 64.3 57.1 62.9

Schillaci et al. [61] 49 Relapse after initial treatment All sites 18F-Choline PET/CT scan 91.7 100 93.9

Marzola et al. [62] 233 Relapse after initial treatment All sites 18F-Choline PET/CT scan 100 97.0 99.0

Kitajima et al. [63] 87 Relapse after initial treatment Local recurrence 11C-Choline PET/CT scan 54.1 92.3 65.5

Kitajima et al. [63] 70 Relapse after initial treatment Lymph nodes 11C-Choline PET/CT scan 90.0 100 92.9

Kitajima et al. [63] 95 Relapse after initial treatment Pelvic bone metastasis 11C-Choline PET/CT scan 81.3 98.7 95.8

Mamede et al. [34] 71 Relapse after initial treatment All sites 11C-Choline PET/CT scan 88.2 98.1 95.8

Ceci et al. [26] 157 Relapse after initial treatment All sites 11C-Choline PET/CT scan 66.2 0 66.2

Tilki et al. [38] 56 Relapse after initial treatment All sites 18F-Choline PET/CT scan 39.7 95.8 82.1

Heesakkers et al. [64] 375 Patients with newly

diagnosed prostate cancer

Lymph nodes MRI 34.0 97.0 NA

Lecouvet et al. [44] 100 Patients with newly


Lymph nodes MRI 82 96 NA

Harisinghani et al. [65] 80 Patients with newly



Wang et al. [66] 411 Patients with newly



Eiber et al. [41] 29 Patients with newly


Lymph nodes MRI 86 85 86

Budiharto et al. [43] 36 Patients with newly


Lymph nodes MRI 18.8 97.6 NA

CT = computed tomography; MRI = magnetic resonance imaging; NA = not available; PET = positron emission tomography.

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with dissection of the suspicious LNs. In that report, all

metastasis-suspicious LNs at PET/CT scan revealed metas-

tases of PCa at pathologic examination. Ten additional

removed LNs, which had not been considered suspicious at

preoperative imaging, did not show recurrence of PCa.

Therefore, the authors concluded that 11C-choline PET/CT

scan represents a useful tool for the detection of PCa LN

relapse. A similar set of patients was examined by Martini

et al. [33], who found that LN relapse was histologically

confirmed in six of eight patients with positive preoperative

11C-choline PET/CT scans. Thus, the authors concluded that

this imaging technique could be useful in selecting optimal

candidates for SLND.

The ability of 11C-choline PET/CT scan to detect clinical

LN relapse appears to be affected by several factors,

including preimaging PSA level, as well as hormonal and

chemotherapy status [14,22,34–36]. Initial reports argued

against the use of 11C-choline PET/CT scan to detect

recurrence in patients with a PSA <5.0 ng/ml because of the

high false-negative results in these individuals [14].

However, these findings were not corroborated in subse-

quent reports that observed a high reliability of 11C-choline

PET/CT scan in detecting tumor recurrence, even in patients

with very low PSA values (ie, <0.5 ng/ml) [22,34,36].

Nonetheless, it appears that PSA kinetics, rather than the

absolute PSA value, should be used to guide the decision to

perform a PET/CT scan. This is especially true for patients

with low PSA values. For example, Castellucci et al. reported

that PSA doubling time (PSA DT) was the only independent

predictor of a positive scan in patients with a PSA level

<2 ng/ml [22]. Likewise, Mamede et al. observed that PSA

DT and hormonal treatment were the only significant

predictors of positive scans in patients with a PSA level

<0.5 ng/ml [34].

In summary, it appears that 11C-choline PET/CT scan

represents a reliable and valid tool for restaging PCa

patients with BCR after initial treatment with curative

intent. However, given the heterogeneity of the currently

available data and the small number of patients exam-

ined, larger studies are warranted to confirm these

promising results. Similar performance characteristics

were reported when 18F-choline was used to detect PCa

relapse (Table 1).

In an interesting report, Passoni et al. [37] studied the

performance characteristics of 11C-choline PET/CT in

patients with BCR after RP who harbored a single suspected

positive LN metastasis. A total of 46 patients were included,

and all received an SLND. Of them, 38 patients (83%)

harbored a positive LN at pathologic examination. However,

only 16 patients (35%) had a pathologic LN metastases

exclusively limited to the nodes indicated by the PET/TC,

and only 11 patients (24%) had an involvement of a single

LN. Based on these findings, the authors concluded that the

performance of 11C-choline PET/CT in detecting a single

positive LN at SLND is poor. Similar results were observed

when 18-fluoroethylcholine PET/CT was used to identify

clinical LN relapse [38]. Therefore, when an SLND is planned

based on PET/CT findings, it must be extended, regardless of

the number of positive LNs on preoperative imaging.


3.1.2. Diffusion-weighted magnetic resonance imaging

In diffusion-weighted MRI (DW-MRI), the Brownian motion

of water protons (molecular diffusion) in biologic tissue is

depicted. Normally, the extracellular and intraductal water

molecules are moving freely in all directions. Therefore,

within the peripheral zone in a healthy prostate, the so-

called apparent diffusion coefficient (ADC), which is

measured by DW-MRI, has high values. Conversely, lower

ADC values are observed in cases of PCa growth [39,40].

Regarding LN staging, DW-MRI seems to have favorable

performance characteristics. Eiber et al. [41] examined the

data on 29 PCa patients (118 LNs were analyzed) who were

investigated with DW-MRI. The performance of DW-MRI in

detecting LNI was calculated using histologic and/or follow-

up data as the standard of reference. These authors used an

ADC cut-off of 1.30 � 10�3 and reported that the sensitivity,

specificity, and discrimination accuracy of this cut-off to

detect LNI were 86%, 85% and 86%, respectively. In a

subsequent report, the same group of authors confirmed

their previous findings in 14 additional PCa patients (55 LNs

were analyzed) [42]. In this report, patients with LNI had

statistically significantly higher ADC values than their

counterparts without LNI (mean ADC: 1.60 � 0.24 vs

1.09 � 0.23 � 10�3, p < 0.001) [42]. Based on these findings,

the authors proposed ADC measured by DW-MRI as a novel

potential imaging biomarker.

Unfortunately, these encouraging results were not

confirmed in other series. Specifically, in a cohort of 36

PCa patients treated with RP and anatomically extended

PLND, Budiharto et al. [43] reported that the sensitivity,

specificity, PPV, and NPV of DW-MRI to detect LNI were 19%,

98%, 46%, and 92%, respectively. These differences in DW-MRI

performance characteristics between the Budiharto et al.

[43] report and the other two aforementioned reports [41,42]

might originate from differences in patient selection criteria

and study design methodology. Indeed, patients described

by Budiharto et al. [43] had a preoperative LNI risk of 10% to

35% according to the Partin tables. Although these patients

harbor high LNI risk, they do not necessarily represent all the

ideal candidates for PLND. It may be argued that these

selection criteria have artificially undermined the perfor-

mance characteristics of DW-MRI. However, given that

Budiharto et al. [43] did not provide a specific ADC cut-off,

a direct comparison of the results of this report with the

previous two studies [41,42] was not possible. Nevertheless,

the major advantage of DW-MRI, when acquired whole-

body, might be the exclusion of the presence of occult bone

metastases with more specificity and sensitivity than with

technetium Tc 99m bone scintigraphy or 11C-choline PET/CT

[44]. Other studies investigating the role of MRI in detecting

LNI are reported in Table 1.

Similar to PET/CT scan, the performance characteristics

of DW-MRI might also be affected by several variables, such

as preimaging PSA value and/or PSA kinetics. However, to

date, there is a paucity of data that examine the impact of

these variables on the accuracy of DW-MRI to detect LNI.

In an interesting study, Thoeny et al. [45] analyzed the

data on 802 removed LNs and reported that the combina-

tion of ultrasmall superparamagnetic particles of iron oxide





(USPIO)–enhanced MRI and DW-MRI allowed the achieve-

ment of optimal performance characteristics in detecting

LNI (sensitivity: 80%; specificity: 87%; PPV: 67%; NPV: 93%;

and accuracy: 90%). In a recent report, the same group of

authors updated their results examining the data on 2993

removed nodes. Fifty-four nodes harbored a metastasis, and

the majority of metastases (93%) were �5 mm in diameter.

The sensitivity, specificity, PPV, NPV, and accuracy of the

procedure were 58%, 83%, 58%, 84%, and 76%, respectively.

As such, the authors concluded that USPIO-enhanced MRI is

accurate in detecting even small metastases. Several USPIO

contrasts had been recently approved in the United States,

Europe, and Japan [46]. However, these contrasts need

further investigation before they can be implemented in

urologic clinical practice.

It is noteworthy that virtually all the aforementioned

reports that discussed the performance of DW-MRI focused

on LN staging in PCa before primary treatment. As such, the

reliability of the technique in detecting clinical LN relapse

after primary treatment is still unknown and warrants

investigation.

3.2. Salvage lymph node dissection in prostate cancer patients

with clinical lymph node relapse after radical prostatectomy

3.2.1. Rationale

The therapeutic benefit of LND has been already established

for several tumors. For example, in the urologic field, LND

represents an important component in the treatment of

patients with testis, penile, and bladder cancer [47,48].

Conversely, the therapeutic role of LND in treating PCa is

still controversial. However, observational data have

showed that PLND might be associated with more favorable

survival rates in PCa patients [9,10], especially when they

harbor a low LNI burden (defined as a maximum of one or

two positive nodes). A recently published randomized trial

showed that at a median follow-up of 74 mo, extended

PLND (in comparison with standard PLND) can significantly

improve the BCR-free rate by 13% and 20% in patients with

intermediate- and high-risk PCa, respectively [49]. Unfor-

tunately, during the last two decades, most patients were

treated with an anatomically limited PLND [11]. Approxi-

mately 30% of patients received no PLND at all [11]. This

situation has certainly resulted in a suboptimal LN

pathologic staging [29–31] and might have contributed to

an increasing risk of clinical LN relapse.

With the development of novel imaging techniques, the

identification of PCa patients with a clinical LN relapse after

primary treatment with RP has become feasible [19,28,32,

41,42,45]. However, these patients are considered by most

experts to harbor a systemic disease, and systemic treatment

with hormonal therapy is recommended in this setting [50].

Some investigators have put forth the provocative hypothesis

that this pattern of recurrence might not necessarily

represent a systemic disease and have suggested that surgical

treatment with SLND might be beneficial in these men

[7,8,32]. The technique, outcomes, morbidity, and mortality

of such a surgical procedure—namely, SLND—represent the

focus of the following part of this review.


3.2.2. Surgical technique and anatomic limits of salvage lymph node

dissection in prostate cancer patients with clinical lymph node relapse

after radical prostatectomy

The currently available literature does not allow an accurate

identification of a standardized SLND surgical technique.

However, some hints can still be derived from the existing

data. Generally speaking, the extent of SLND and its

anatomic limits can be guided by the results of 11C-choline

PET/CT scan and/or other preoperative staging imaging. In

patients with clinical LN relapse limited to the pelvic zone, it

is preferable to perform an SLND that includes the fibrofatty

tissue along the external iliac vein, with the distal limit at

the deep circumflex vein and femoral canal. Proximally,

SLND can be extended to include all the LNs along the

common iliac vessels up to the aortic bifurcation. All

fibrofatty tissue within the obturator fossa should also be

removed. Likewise, presacral LNs and LNs located laterally

and medially to the internal iliac artery must be excised

[51].

In patients with retroperitoneal clinical LN relapse at

preoperative imaging and/or in patients with positive

common iliac nodes at intraoperative frozen section

analysis, SLND can be extended to the retroperitoneal

region. This procedure usually consists of the excision of all

nodal tissue located between the renal artery (cranially) and

aortic bifurcation (caudally). Medial and lateral limits

usually consist of the midline of the vena cava and right

ureter, as well as the midline of the aorta and left ureter.

Sometimes it might be necessary to remove the inter-

aortocaval LNs as well. It is of note that clinical LN relapse

may involve several nodes other than those indicated by

the PET/CT scan [37,38]. Thus, some surgeons prefer to

perform a pelvic and retroperitoneal LND upfront, regard-

less of the positive zone on the scan. However, unless clearly

indicated by the preoperative imaging, it might be wise to

avoid LND in areas that were included in the primary LND

and/or included in adjuvant/salvage radiotherapy treat-

ment. Trying to dissect these nodes might be extremely

tedious, and such dissection is unlikely to uncover the

presence of malignancy.

The aforementioned description of SLND closely agrees

with the personal experience of the authors. However, it is

noteworthy that the description is based on currently

available expert opinion, which consists mainly of retro-

spective small institutional studies. The correct technique

of SLND, the anatomic limitations, and the exact indications

are controversial subjects that warrant future investigation.

3.2.3. Cancer control outcomes in patients treated with salvage

lymph node dissection

Data regarding the oncologic outcomes of SLND in patients

with clinical LN relapse are continuously growing. However,

the number of patients treated with this technique, as well

as the available follow-up, is still limited. One of the first

reports that addressed this end point examined the data on

15 patients affected by BCR after primary PCa therapy

associated with 11C-choline PET/CT scan evidence of nodal

recurrence [18]. In this report, all patients had at least one

PET/CT scan with positive LN and no evidence of local



Table 2 – Studies including patients with lymph node–recurrent prostate cancer treated with salvage lymph node dissection

Study Patients,no.

PSA atSLND, ng/ml,

mean

Nodesremoved,no., mean

Positivenodes,

no.,mean

Gleasonscore

Completeresponse,

%*

Follow-upperiod, mo,

mean

5-yrBCR-free

survival, %

5-yrprogression-

freesurvival, %

5-yrcancer-specific

survival, %

Rinnab et al. [18] 15 1.7 13.9 NA NA NA 13.7 NA NA NA

Winter et al. [32] 6 2.0 NA NA NA NA 24** NA NA NA

Martini et al. [33] 8 1.6 11.6 1.0 2–6: 25%

7: 37%

8–10: 38%

NA NA NA NA NA

Schilling et al. [28] 10 10.9 7.1 2.8 2–6: 20%

7: 60%

8–10: 20%

NA NA NA NA NA

Rigatti et al. [8] 72 3.7 30.6 9.8 2–6: 18%

7: 44.4%

8–10: 37.6%

56.9 39.4 19 34 75

Jilg et al. [7] 52 3.9 23.3 9.7 2–6: 23%

7: 46%

8–10: 31%

46 35.5* 9 26 78

Suardi et al. [53] 162 3.6 24.6 6.1 NA 40.7 29.2 40 47 86

Suardi et al. [52] 59 3.9 29.5 8.9 2–6: 20.3%

7: 44.1%

8–10: 35.6%

59.3 81.1 29.4 52.0 89.1

BCR = biochemical recurrence; NA = not available; PSA = prostate-specific antigen; SLND = salvage lymph node dissection.* Complete biochemical response was defined as a PSA value <0.2 ng/ml after surgery.** Median.



recurrence or bone metastases. Patients underwent SLND,

with a mean number of 13.9 LNs removed. Mean and

median PSA values at treatment were 1.7 and 1.7 ng/ml,

respectively. Only 1 of the 15 patients had a PSA nadir

<0.1 ng/ml after SLND. Patients were followed up for a

mean time of 13.7 mo, and three patients developed bone

metastases. The authors concluded that although limited in

sample size and follow-up time, their data suggest that the

benefit that can be obtained through 11C-choline PET/CT

scan and subsequent SLND is rather small [18].

In a subsequent report, Winter et al. [32] investigated the

data on six PCa patients with BCR after primary treatment

with RP. All patients had a single positive LN metastasis at

PET/CT scan without evidence of local relapse or distant

metastasis. All these patients were treated with SLND.

Median PSA value at treatment was 2.04 ng/ml (range:

0.67–4.51). All metastasis-suspicious LNs at PET/CT scan

were histologically confirmed. The 10 LNs that were

additionally removed were all correctly negative for cancer.

Patients were followed for a median of 24 mo (range:

21–35). During this period, three patients showed a durable

PSA remission (<0.01 ng/ml [n = 2] and<0.03 ng/ml [n = 1])

without adjuvant therapy. Despite the very limited patient

numbers and follow-up, this study showed that SLND

might be beneficial, at least in a select group of patients

(ie, patients with a single positive spot at PET/CT scan). The

authors of this report argued that only suspicious nodes on

11C-choline PET/CT scan should be removed, as no cancer

was detected in the additionally removed nodes. However,

these findings were not confirmed in a subsequent report

that examined a substantially larger sample size and

observed that LN metastasis frequently involves nodes

other than those detected by PET/CT scan [37,38].

In one of the largest series reported to date, Rigatti et al.

[8] analyzed the data on 72 patients with BCR after RP


associated with clinical LN relapse at PET/CT scan, without

local and/or distant metastasis (Table 2). The preoperative

mean and median PSA values were 3.7 and 1.5 ng/ml,

respectively. At SLND, the mean and median numbers of

removed LNs were 30.6 and 29, respectively. The mean and

median numbers of positive LNs were 9.8 and 2, respec-

tively. Forty-one patients (57%) achieved a complete

biochemical response after surgery, which was defined as

a PSA <0.2 ng/ml at 40 d from SLND. Of these patients, 13

(32%) received adjuvant hormonal therapy, and 28 (68%) did

not receive adjuvant hormonal therapy during the follow-

up (mean: 39.4 mo; median: 39.8 mo). Of patients with

complete biochemical response and no adjuvant hormonal

therapy, a further PSA progression was observed in

24 patients (86%). This finding corresponded to a 5-yr

BCR-free survival rate of 19%. In the entire cohort (n = 72),

the 5-yr clinical recurrence-free survival and cancer-

specific survival rates were 34% and 75%, respectively. In

a recent study [52], the same authors updated their

findings, focusing exclusively on patients with �5 yr of

follow-up. Of 59 patients included in this report, 35 patients

(59.3%) had complete biochemical response after surgery.

Among these patients, the 5- and 8-yr BCR-free survival

rates were 29.4 and 22.1%, respectively. The 5- and 8-yr

clinical recurrence-free survival rates were 52.0% and 38.2%,

respectively. Finally, the 5- and 8-yr cancer-specific survival

rates were 89.1% and 80.6%, respectively.

In another report, Jilg et al. [7] examined the data on

52 patients with BCR after primary treatment with curative

intent associated with clinical LN relapse at PET/CT scan,

without distant metastasis. Patients were excluded if they

received radiotherapy after primary treatment and before

SLND. The preoperative mean and median PSA values were

3.9 and 1.1 ng/ml, respectively. At SLND, the mean and

median numbers of removed LNs were 23.3 and 17,





respectively. Mean and median numbers of positive LNs

were 9.7 and 4, respectively. Complete biochemical

response, defined as a PSA value <0.2 ng/ml after surgery,

was achieved in 24 of 52 cases (46%). In 27 of 52 cases (52%),

adjuvant radiotherapy was performed after SLND. A mean

dose of 50.8 Gy (standard deviation [SD]: 3.6) was applied

per patient externally in the anatomic region in which

positive LNs had been confirmed histologically. In six

patients, based on PET/CT findings with additional evidence

of local PCa recurrence in prostatic fossa, a mean dose of

68.7 Gy (SD: 2.39) was locally applied. The median follow-

up of this cohort was 35.5 mo. A total of 24 patients (46%)

had complete biochemical response after surgery, followed

by 1-yr BCR-free survival of 71.8%. In the entire cohort

(n = 52), the 5-yr clinical recurrence-free survival and

cancer-specific survival rates were 26% and 78%, respec-

tively.

Finally, in the only multi-institutional report available to

date, Suardi et al. [53] examined the data from five tertiary

referral centers of 162 patients affected by BCR after RP

associated with nodal recurrence detected at either 11C-

choline PET/TC scan or conventional imaging. The preoper-

ative mean and median PSA values were 3.6 and 1.9 ng/ml,

respectively. At SLND, the mean and median numbers of

removed LNs were 24.6 and 20.0, respectively. The mean

and median number of positive LNs were 6.1 and 2,

respectively. A total of 132 patients (81%) were found to

harbor a pathologically confirmed clinical LN relapse, and

66 patients (41%) achieved a complete biochemical

response after surgery [53].

Taken together, the current data denote that SLND is

feasible and can be used as an option to treat patients with

clinical LN relapse after primary treatment with RP.

However, a significant proportion of patients treated with

this technique will invariably progress to BCR after surgery.

Nonetheless, at 5 yr, approximately 9–19% of these patients

will remain free from BCR, and approximately 26–34% will

remain free from clinical recurrence. These data indicate

that the benefit of SLND in the majority of cases would be to

prolong survival and/or to postpone hormonal therapy, but

not to achieve a complete cure. However, whether or not

this survival benefit would compare preferentially with the

current standard of care (ie, hormonal therapy) is still

unknown because of the lack of comparative data between

these two treatment modalities. Nonetheless, given the

limited survival benefit of hormonal therapy, SLND might

represent a supplementary, and not a substitutive, treat-

ment option.

3.2.4. The importance of patient selection

Despite the limited data available, it appears that SLND

could be beneficial only in a select group of patients. This

idea highlights the importance of correct patient selection

before surgery. Rigatti et al. [8], as well as Jilg et al. [7],

defined several factors that can be helpful in identifying the

best candidates for SLND. Rigatti el al [8] observed that the

5-yr clinical recurrence-free survival was higher for patients

with a preoperative PSA value <4 ng/ml compared with

patients with a PSA �4 ng/ml (48% vs 13%; log-rank:


p = 0.004). Conversely, the 5-yr clinical recurrence-free

survival was lower for patients with positive nodes in the

retroperitoneum compared with patients with positive

nodes in the pelvis only (11% vs 53%; p < 0.001). These data

were confirmed in the multivariable analyses, in which

preoperative PSA >4 ng/ml (hazard ratio [HR]: 2.13;

p = 0.03) and the presence of retroperitoneal uptake at

PET/CT scan (HR: 2.92; p = 0.004) were independent

predictors of clinical progression after surgery. Additionally,

Jilg et al. [7] defined a Gleason score of 8–10 (HR: 3.5;

p = 0.03) as an independent predictor of clinical progres-

sion.

Several postoperative factors, including complete bio-

chemical response, the location of positive LNs at SLND, and

the number of positive LNs at SLND, were established as

independent predictors of clinical progression [7,8]. Al-

though these variables can be helpful for postoperative risk

classification and patient counseling, they cannot be used in

selecting the best candidates for surgery preoperatively.

In summary, correct patient selection for SLND is

essential to achieve acceptable cancer control outcomes

and avoid unnecessary morbidity in a significant proportion

of patients. Patients with a low PSA value (<4 ng/ml), well

to moderately differentiated tumor (Gleason score �7), and

a clinical LN relapse limited to the pelvis only might

represent the ideal candidates for SLND. However, a larger

sample size and more homogenous cohorts are necessary to

allow the development of a multivariable tool that can

improve the accuracy of patient selection. Larger cohorts

may allow the identification of other survival predictors. For

example, clinical experience suggests that patients with

biochemical progression despite hormonal therapy are at a

higher risk of mortality. These individuals could not benefit

from SLND. Likewise, age might represent another impor-

tant factor that influences SLND outcomes, while most of

the currently available reports included young and highly

selected patients. Thus, it might be difficult to evaluate the

impact of these factors using the currently available

literature. Older patients might benefit from treatment

modalities other than surgery, such as intensity-modulated

radiation therapy, for the management of clinical LN

relapse. However, data regarding the long-term outcomes

of this modality are scarce and beyond the scope of this

review.

3.2.5. Complications associated with salvage lymph node dissection

Two studies used a systematic way to report the data

regarding postoperative morbidity and mortality in patients

treated with SLND [7,8] Complications were stratified

according to Clavien classification. It is encouraging to

note that most of the reported complications were mild.

Indeed, the most frequent complication was lymphorrhea

(15.3%), followed by fever (14.5%) and ileus (11.2%). High-

grade (Clavien 3b) complications were rare and consisted of

ureteral injury in one case (0.8%) and the necessity of

surgical reintervention in two cases (1.6%). Other complica-

tions, such as lymphoceles and limb lymphedema, might

also occur after SLND. However, these complications were

not reported by the previous two studies [7,8]. This





situation might stem from the fact that these morbidities are

frequently mild and self-limiting. Nonetheless, they should

be considered, and patients should be informed accordingly.

To date, no postoperative mortality was reported after SLND

[7,8]. These data denote that this procedure is feasible and

has an acceptable safety profile. However, larger studies are

warranted to validate these observations. It is noteworthy

that these data originate from tertiary care centers and might

not be generalizable to the community setting. However, we

believe that for the time being, such a delicate and

experimental surgical procedure should be offered only in

high-volume centers and by expert surgeons.

4. Conclusions

The current data, although limited, indicate that PSA

kinetics, especially PSA DT, should guide the decision to

perform PET/CT scan and/or DW-MRI in patients with

suspected clinical LN relapse. For the majority of patients,

SLND might help in postponing hormonal therapy. Indeed,

about half of patients treated with SLND will have an

immediate complete postoperative biochemical response,

and roughly one-third of these patients will remain free

of biochemical relapse for 5 yr. Patients with a PSA value

<4 ng/ml, Gleason score �7, and clinical LN relapse limited

to the pelvis might benefit the most from this procedure.

However, these findings still need to be validated using

rigorous methodology and prospective randomized data.

Author contributions: Firas Abdollah 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: Abdollah, Briganti, Montorsi, Stenzl, Stief,

Tombal, Van Poppel, Touijer.

Acquisition of data: Abdollah, Touijer.

Analysis and interpretation of data: Abdollah, Briganti, Montorsi, Stenzl,

Stief, Tombal, Van Poppel, Touijer.

Drafting of the manuscript: Abdollah, Touijer.

Critical revision of the manuscript for important intellectual content:

Briganti, Montorsi, Stenzl, Stief, Tombal, Van Poppel, Touijer.

Statistical analysis: None.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Briganti, Montorsi, Stenzl, Stief, Tombal, Van Poppel, Touijer.

Other (specify): None.

Financial disclosures: Firas Abdollah 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.

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