








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Prostate cancer, radical prostatectomy, lymph 
node dissection

None declared. Received on July 26, 2021 
Accepted on August 27, 2021

Soc Int Urol J.2021;2(6):347–353

DOI: https://doi:10.48083/HAHE3801

347SIUJ.ORG SIUJ  •  Volume 2, Number 6  •  November 2021

ORIGINAL RESEARCH

Protocol for a Pilot Study of the NODE Trial,  
a Prospective Multicentre Randomised Trial  
of Extended Pelvic Lymph Node Dissection  
for High-Risk Prostate Cancer
George McClintock,1 Hadia Khanani,1 Antonella De Rosa,2 Scott Leslie,1,2,3 Nariman Ahmadi,1  
Jeremy Fallot,1 Peter Ferguson,2,4 Henry Woo1,3

1 Chris O’Brien Lifehouse Hospital, Camperdown, Australia 2 Royal Prince Alfred Hospital, Camperdown, Australia 3 The University of Sydney, Camperdown, Australia 
4 The University of Sydney Medical School, Sydney, Australia

Abstract

Objectives To test the hypothesis that a randomised trial of extended pelvic lymph node dissection (ePLND) can 
recruit at a rate acceptable for a larger scale trial.
To compare the following secondary endpoints between the 2 arms: the rate of protocol violations, the intraoperative 
and postoperative morbidity of ePLND, and complications, and to evaluate short-term oncological outcomes 
comparing biochemical recurrence, clinical recurrence, and survival between arms.

Patients and Methods A pilot study will be undertaken at Chris O’Brien Lifehouse and Royal Prince Alfred 
Hospitals for the NODE trial. Twenty patients will be randomised 1:1 to radical prostatectomy with or without 
ePLND. Eligible participants will have high-risk prostate cancer and will be scheduled for robotic radical 
prostatectomy. High-risk disease will be defined as in the 2019 NCCN guidelines (stage ≥ T3a, ISUP Grade Group ≥ 4 
or PSA ≥ 20ng/mL). PSMA PET/CT staging not showing any extraprostatic disease will be required.
Quality control measures to ensure consistent delivery of high-quality extended lymph node dissections are in place, 
and surgeons have been selected for their consistent ability to perform such procedures.

Results The trial is currently underway.

Conclusion On current available evidence, it is unclear if ePLND provides additional benefit over radical 
prostatectomy.

Introduction

Prostate cancer is one of the most commonly diagnosed cancers in men; however, the basic question of whether 
to perform a lymph node dissection at the time of radical prostatectomy remains unanswered. Pelvic lymph node 
dissection (PLND) is the most accurate test for staging and prognosis[1,2] and has substantial theoretical plausibility 
for survival benefit by removing micro-metastases in lymph node confined disease. There is, however, no robust 
evidence to support improved survival or improvement in other oncological outcomes[3].

Because of the lack of a sentinel node and the wide bilateral primary drainage area, an adequate PLND is a signif-
icant undertaking[4], and current guideline recommendations to perform the procedure are based on limited 
evidence[5].



The current literature is affected by multiple issues 
including a lack of standardisation of definitions and 
a preponderance of retrospective data. The extent of 
PLND (limited, standard, and extended) and anatomi-
cal boundaries vary between surgeons and centres, and 
evidence regarding both harms and benefits of PLND is 
conflicting[3]. Extended lymph node dissection consis-
tently yields more lymph nodes, which would theoreti-
cally offer a larger therapeutic benefit, although there is 
little high-quality evidence for this either.

Risks and benefits
PLND is associated with a higher risk of lymphocele 
and longer operative time[6,7]. Limited evidence 
exists for other purported risks including increased 
risk of lymphoedema, mortality, and worse functional 
outcome s (u r i na r y i ncont i nenc e a nd erec t i le 
dysfunction)[3]. A recent systematic review by Fossati et 
al. 2016, evaluated the benefits and harms of PLND, in 
which the primary outcome measures were biochemical 
recurrence, clinical recurrence, and survival. Overall, 
the quality of the evidence was low, and the risk of bias 
high. Three randomised control trials were available, 
of which one was reported as conference abstracts 
only[8,9], and only 4 of the remaining studies were 
performed prospectively. Evidence is very mixed 
regarding risks and benefits. Twenty-one retrospective 
studies compared oncological outcomes in no PLND 
with those in any form of PLND. None of the studies 
showed statistically significant differences in support of 
PLND for biochemical recurrence, distant metastases, 
or survival. Eight studies compared limited/standard 
PLND with extended PLND (ePLND) with conflicting 
results. There is some evidence of therapeutic benefit 
however, patients undergoing PLND showing lower 
biochemica l recurrence rates and an additiona l 
retrospective study showing the removal of higher 
number of lymph nodes being associated with better 
cancer specific survival.

Two RCTs have been published in this area. The first[10] 
recruited 291 patients with intermediate- or high-risk 
prostate cancer, who were randomly assigned to undergo 
ePLND on one side of the pelvis and limited PLND on 
the other. After a median follow-up of 35.2 months, 
ePLND was associated with better tumour staging and 
increased morbidity. The second, more recent study[11] 
found no difference between the groups, though a post 

hoc subgroup analysis found improvement in outcomes 
in patients with higher Gleason grade cancers.

Currently, the European Association of Urology 
(EAU) guidelines recommend performing an ePLND in 
high-risk patients and not performing limited or stan-
dard dissection at all[5]. Limited dissection exposes the 
patient to additional risk of harm, but it will miss many 
nodal metastases and is associated with a significant risk 
of understaging. All patients recruited into this study, 
by virtue of meeting the NCCN guidelines definition of 
high-risk prostate cancer, also meet criteria in the EAU 
guidelines to recommend ePLND[12], thus the experi-
mental arm in this trial is actually the no ePLND arm, 
with ePLND forming standard of care.

Extent of dissection
Lymph node metastases from the prostate are highly 
variable, and the impact of the extent of dissection on 
outcomes reported by previous studies is unclear.

Although definitions vary, limited PLND is most 
commonly defined as the removal of nodal tissue from 
the area along the external iliac vein and above the obtu-
rator nerve; standard PLND is area covered by limited 
PLND plus the area below the obturator nerve and onto 
the internal iliac vessels; ePLND as removal of all nodes 
overlying the external iliac artery and vein, within the 
obturator fossa, and medial to the internal iliac artery.

The current definitions are somewhat arbitrary in their 
extent, and novel mapping study methods of lymph node 
drainage have shown that nodal drainage patterns are 
wider than previously described and extend well beyond 
the obturator region[4]. On the basis of these studies, 
a standard dissection is likely to remove only 38% of 
primary draining lymph nodes, but concerningly even 
the recommended extended lymph node dissection will 
remove only 63%, thus a new nodal dissection template 
is required.

The lack of level 1 evidence to support the therapeutic 
role of PLND highlights the need for a robust, adequately 
powered RCT. The aim of this pilot study is to determine 
the feasibility of the randomised trial design before the 
development of a full-scale RCT.

Patients and Methods
The NODE trial is a planned multicentre randomised 
control trial of ePLND. This protocol is for a pilot study 
assessing the ability of such a trial to recruit patients 
in a timely fashion and to determine plausibility given 
previous difficulties with other similar trials.

Three surgeons at 2 institutions will recruit patients 
over a 12-month period. The recruitment target is 20 
patients, chosen without reference to any previous trial 
recruitment data, as none are available. Numbers of 

Abbreviations 
ePLND extended PLND
ISUP International Society of Urological Pathology
PLND pelvic lymph node dissection
PSMA prostate specific membrane antigen

348 SIUJ  •  Volume 2, Number 6  •  November 2021 SIUJ.ORG

 ORIGINAL RESEARCH



eligible patients and reasons for non-participation will 
be recorded.

Surgeons in this study have a documented history 
of performing high-quality ePLND, 2 are fellowship 
trained robotic surgeons and the third has > 20 years’ 
experience performing open and robotic radical prosta-
tectomy.

The primary and secondary objectives are listed in  
Table 1.

The study is approved (2019/ETH09765) by the 
Sydney Loca l Hea lt h District Human Research 
Ethics Committee (EC00113) and is registered on 
the Australian New Zealand Clinical Trials Registry 
(ACTRN12620000881932). This pilot study will require 
no funding. It will be conducted according to local laws 
and regulations, the Declaration of Helsinki, and the 
principles of good clinical practice. The trial schema is 
outlined in Figure 1.

Recruitment and randomisation
Patients w il l be screened for recruitment af ter 
histological diagnosis of prostate cancer has occurred. 
Patients will be assessed for eligibility using the inclusion 
and exclusion criteria listed in Table 2.

The standard of care in Australia for staging high-risk 
prostate cancer is to perform a PSMA PET/CT. Patients 
with non-metastatic disease on PSMA PET will form the 
population to be evaluated in this study.

Patients will be randomised 1:1 to robotic radical 
prostatectomy without PLND (experimental arm) or 
to robotic radical prostatectomy with bilateral ePLND 
(standard of care). The participating surgeons in this 
trial share the opinion that the current evidence has 
not shown superiority of either approach and thus the 
2 arms of the trial are at equipoise. The trial will be of 

349SIUJ.ORG SIUJ  •  Volume 2, Number 6  •  November 2021

Protocol for a Pilot Study of the NODE Trial

TABLE 2. 

Inclusion and exclusion criteria[12]

Inclusion Criteria

• Histologically proven prostate cancer scheduled for robotic assisted 
radical prostatectomy

• PSMA PET negative for metastatic disease

• Non-metastatic, high-risk, or very high-risk disease  
(2019 NCCN Guidelines), consisting of any of:
• Stage ≥ T3a or
• ISUP Grade Group ≥ 4, or
• PSA ≥ 20ng/mL

Exclusion Criteria

• History of deep venous thrombosis

• History of lower limb lymphedema

• History of previous pelvic radiotherapy

• PSMA: prostate specific membrane antigen; NCCN: National 
Comprehensive Cancer Network; ISUP: International Society of 
Urological Pathology.

TABLE 1. 

Primary and secondary objectives

Primary

To determine the proportion of eligible patients for which trial 
participation is achieved and to assess the rate of recruitment of 
eligible patients 

Secondary

To determine the incidence and nature of protocol violations

To evaluate the morbidity of PLND including complications, 
intraoperative and postoperative outcomes, and postoperative 
morbidity

To evaluate the short-term oncological outcomes assessed by 
biochemical recurrence, clinical recurrence, and survival

FIGURE1.

Flow diagram

Screening of patients Ineligible

Eligible patients approached
by trial investigators

Non-participation -
reasons recorded

Randomisation

Robotic 
prostatectomy 
without PLND

Robotic 
prostatectomy 

with ePLND

Intraoperative data collection 
and review of procedure 

performed, including 
photographs

Postoperative data collection



open label design. Data will be analysed on an intention 
to treat basis.

Intraoperative protocols
Robotic radical prostatectomy will occur at Royal Prince 
Alfred Hospital or Chris O’Brien Lifehouse.

The ePLND template is represented diagrammatically in 
Figure 2 and consists of removal of lymph nodes located 
along the external iliac vein, those in the obturator 
fossa and along the internal iliac artery up to the mid-
common iliac region where the ureter crosses the iliac 
vessels, those that are dorsolateral to the external iliac 
vessels and at the bifurcation of the common iliac 
vessels, in the fossa of Marcille, and on the medial aspect 
of the internal iliac vessels.

To ensure quality of surgical resection, 3 still photo-
graphic images will be taken for each side:

• Photo 1:  medial view showing internal, external, and 
common iliac vessels

• Photo 2: space between external iliac vein and artery
• Photo 3:  lateral view (by medial retraction of the 

external iliac vessel) to show the deep obtur-
ator space and fossa of Marcille.

These photographs will be reviewed by the researchers 
at the conclusion of the study. Failure to adequately 
dissect the structures or document their dissection will 
be considered a protocol violation.

All patients will have a pelvic drain inserted at the time 
of surgery.

Perioperative, operative, and postoperative data will be 
recorded, as per fields outlined in Table 3.

Histopathology
Lymph node specimens will be submitted separately by 
drainage region for right and left side as external iliac, 
internal iliac, common iliac, and fossa of Marcille. The 
histopathology will be reviewed at the Department of 
Tissue Pathology and Diagnostic Oncology at Royal 
Prince Alfred Hospital by specialist uropathologists. 
All the submitted nodal tissue will be embedded for 
microscopic analysis.

Follow-up
Following discharge, patients will be followed up by their 
urologist. They will have planned follow-ups at 4 weeks, 
3 months, 6 months, and 12 months postoperatively, 
with a PSA test before each appointment.

Sample size and power calculation
No sample size or power calculation was performed 
for this study given its nature as a pilot study. Twenty 
patients will be recruited, or if <20 patients are recruited 
after 12 months, recruitment will cease, and patient 
numbers will be capped at that level.

Results
Recruitment
The ability of this pilot study to recruit patients for a 
larger trial forms the primary outcome. This will be 
reported as a proportion of eligible patients who are 
successfully enrolled and randomised. Reasons for non-
enrolment of eligible patients will be recorded. Failure 
to recruit the target number of patients will not preclude 
progression to a larger trial, but may influence its design.

Protocol violations
Performing the large lymph node dissection required 
in this study consistently while maintaining a high 
standard will add significant time and complexity to 
the procedures. Monitoring both the intraoperative 
and postoperative rate of study protocol violations will 
therefore ensure that this approach can be successfully 
deployed in a larger trial. Protocol violations will be 
reported by procedure stage and nature.

Adverse events
Intraoperative, immediate postoperative and post 
discharge adverse events will be reported in both arms 
using the Clavien-Dindo classification.

Oncological outcomes
The occurrence of biochemical recurrence (serum PSA ≥ 
0.2ng/mL[13,14]), clinical (radiological) recurrence, and 
survival time will be recorded between the 2 arms.

Discussion
There are a number of causes of the current lack of 
clarity regarding the therapeutic benefit of pelvic lymph 
node dissection.

FIGURE 2.

Extended PLND template

The orange, yellow and green regions represent the external, internal, 
and common iliac regions, respectively. Dashed lines indicate the 
fossae of Marcille.

Reprinted with permission from Maderthaner et al. “More extended 
lymph node dissection template at radical prostatectomy detects 
metastases in the common iliac region and in the fossa of Marcille.” 
BJU Int. 2018 May;121(5):725-731.

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As discussed above, no trials comparing ePLND with 
no PLND have been reported. Of the 2 published RCTs, 
one randomised patients to one side extended and one 
side limited dissection, limiting its ability to provide 
prognostic data[10]. A second RCT[11] has reported no 
significant difference between limited and extended 
PLND, but on post hoc subgroup analysis, found it to be 
beneficial in patients with higher Gleason scores. Multi-
ple factors make randomised trials in this area difficult, 
and clear level 1 evidence is lacking as a result.

Difficulties inherent in surgical randomised trials 
are exacerbated for trials of PLND in prostate cancer. 
Despite a lack of proven therapeutic benefit, pelvic 
lymph node dissection has substantial biological plau-
sibility and forms a widespread component of surgical 
practice. Reluctance to have patients randomised to 
one arm of a trial is a common impediment to surgical 
trials, and many surgeons would feel uncomfortable 
not performing a lymph node dissection on high-risk 
patients.

Performing large pelvic lymph node dissections is 
also time-consuming and difficult, and participating 
surgeons need to be motivated to perform an adequate 
dissection. A large, bilateral lymph node dissection is 
likely to add significantly to the length of a case, even in 
the hands of a surgeon experienced at performing the 
procedure. It requires dissection around the large blood 
vessels of the pelvis, and this may be outside skill set of 
many surgeons, especially if performed robotically. For 
this reason, the intraoperative photographs have been 
included, in an attempt to monitor and maintain dissec-
tion quality.

Trials in this area have previously had difficulty 
recruiting[15]; given this and the above reasons, it is 
prudent to perform a pilot study.

Previous trials comparing limited with ePLND 
may have been easier to perform, and they sidestepped 
the potential ethical issue of not performing a PLND 
in high-risk patients, but their trial design is not the 
right one for answering this question. The current 
state of the literature is that there is no level 1 evidence 
for the performance of lymph node dissection, and 
the inclusion of a limited PLND is likely only to act 
as a confounder. There is good evidence that ePLND 
provides superior staging, and the EAU guidelines thus 
recommend performing an ePLND if any lymph node 
dissection is going to be performed. Regarding the ethi-
cal issue of not performing a PLND at all compared with 
a limited dissection, limited PLND is a procedure with 
the risks but not the benefits of a larger dissection, and 
should thus be regarded as inferior to both ePLND and 
no dissection[16].

Patient selection needs to be judicious to ensure the 
highest likelihood of showing, or definitively disprov-

351SIUJ.ORG SIUJ  •  Volume 2, Number 6  •  November 2021

Protocol for a Pilot Study of the NODE Trial

TABLE 3. 

Data collected

Patient characteristics

• Age
• Comorbidities and 

medications

• Charlson comorbidity  
index

Cancer characteristics

• ISUP Grade Group
• PSA
• Local clinical T stage
• Briganti nomogram % 

chance of lymph node 
involvement

• MRI
• PSMA PET/CT
• Other imaging

Intraoperative

• Operative time (total)
• Operative time (console 

time)
• Estimated blood loss
• Blood transfusion
• Correct procedure 

performed as per 
randomisation 

• If randomised to ePLND,  
as per template?

• Still photographs of  
extent of PLND

• Use of drain

Postoperative

• Postoperative duration of 
hospital stay

• Complications: early (< 30 
days) and late (< 90 days)

• Duration of catheterisation 

• Duration of pelvic drain
• 30-day readmission
• 90-day mortality

Pathology

• Weight of gland
• Gleason score/ISUP Grade 

Group
• Tumour volume
• Extraprostatic extension
• Seminal vesicle invasion
• Surgical margin status
• Lymphovascular invasion

• Periprostatic fat lymph 
node status

• Numbers of lymph nodes 
dissected

• Nodal metastases
• Presence of ductal 

carcinoma

Oncological outcomes 

• Biochemical failure (PSA)
• Clinical recurrence 

(radiological evidence of 
localised recurrence or 
distant metastases)

• Survival (alive at one year 
or date of death)

Morbidity/ complications > 90 day 

• eg, thromboembolic events/ lymphocele/ lymphoedema, 
neuropraxia, other

ISUP: International Society of Urological Pathology; PSMA: prostate 
specific membrane antigen.



ing, a benefit of PLND. Patients with no lymph node 
metastasis will derive no benefit from PLND, nor are 
those with established distant metastatic disease likely 
to benefit, as their prognosis will be substantially deter-
mined by their distant disease. Patients with high risk of 
lymph node metastases but the lowest chance of distant 
metastatic disease are thus the ideal target population.

With reference to targeting this population, it is likely 
that multiple factors have overlapped to make previ-
ous trials inadequately powered to detect differences in 
outcomes. New technology in the form of PSMA scans 
and new research in the form of the above-mentioned 
technetium node mapping studies may allow this to be 
addressed in this trial.

Importantly, previous trials in this area have not used 
PSMA staging. Data from the recent proPSMA study 
has shown that traditional staging (CT and bone scan) 
fails to detect distant metastatic disease in two-thirds 
of cases[17]. Previous studies would have included these 
patients as they would have been staged as having local-
ised disease. These patients will not benefit from local 
treatment, and although randomisation would ensure 
they were evenly distributed, their inclusion would lead 
to significant dilution of the effect of any lymph node 
dissection.

PSMA accurately predicts the presence of lymph node 
metastases[18]. However, in patients with lymph node 

metastases identified on PSMA, biochemical recur-
rence rates approach 50%, even in patients treated with 
ePLND[19], pointing to the presence of micrometa-
static disease outside the pelvis. The selection of patients 
with no extra prostatic disease on PSMA aims to select 
patients who have only early nodal disease and thus use 
the greater accuracy from this new modality to target 
patients with the best likelihood of surgical cure.

The extent of dissection chosen in previous retrospec-
tive and prospective studies is also likely to have diluted 
previous evidence of effect. The publication of data 
indicating that for clearance of 75% of draining lymph 
nodes[4] a bilateral ePLND must be performed indicates 
that previous trials would have diminished effect size 
by missing as much as half of lymph node metastases. 
A trial assessing dissection matching this new mapping 
pattern is required.

As a pilot study, this study has many limitations. To 
test recruitment and the suitability of the protocol in 
a reasonable amount of time, this study has been kept 
intentionally small, with few patients, surgeons, and 
centres. If the study is converted to a full randomised 
control trial, these limitations will be addressed.

The pilot study of the NODE trial has commenced 
recruitment and aims to complete recruitment within 
12 months. The protocol may be altered before the 
commencement of the NODE trial proper.

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