Download Pelvic Lymph Node Dissection in Prostate Cancer: Indication, Extent

Pelvic Lymph Node Dissection in Prostate Cancer:
Indication, Extent, and Therapeutic Role
in the Contemporary Era
1,2Kwang
2Department
1Department of Urology, Ewha Womans University Mokdong Hospital
of Urology, Urologic Science Institute, Yonsei University College of Medicine
Abstract
Recently, fewer pelvic lymph node dissections (PLNDs) have
been performed in the treatment of prostate cancer; this decrease
may be attributable to stage migration and an increased use of
minimal invasive surgery. Nevertheless, PLND remains the
most accurate methods for detecting lymph node metastasis;
furthermore, patients with lymph node metastasis who
undergo PLND demonstrate favorable long term outcomes.
The decision to perform PLND is based on a predictive
model. Current models rely upon various nomograms which
originate from an extended series of PLNDs. Although recent
imaging modalities have demonstrated improved diagnostic
accuracy, PLND should not be omitted in patients showing
negative results in image studies. To assess the adequacy of
PLND, anatomical templates are more important than total
Keywords: prostatic neoplasm; prostatectomy;
lymph node excision (MeSH)
# Dr.
Hyun Kim#, 2Sung Joon Hong, 2Koon Ho Rha
lymph node counts. It is generally agreed that PLND should
be performed in patients with risk of lymph node metastasis
using extended templates; these templates include not only the
external iliac and obturator area, but also the internal iliac
area. Despite improved staging accuracy, removing lymphatic
tissue from the presacral area may affect functional outcomes
after surgery. Primary lymphatic landing sites also include the
common iliac area, which can be a route to the retroperitoneal
lymph nodes. A growing body of evidence suggests that PLND
improves oncologic outcomes, and a recent randomized
controlled trial demonstrated that PLND improves biochemical
outcomes in patients with intermediate and high risk prostate
cancer. The long term oncologic outcomes of PLND treatment
should be investigated in further studies.
Introduction
The widespread application of the prostate-specific
antigen (PSA) test has resulted in early detection of
prostate cancer and a decreased incidence of lymph node
metastasis. The incidence of lymph node metastasis was
20-40% in patients undergoing surgery before the PSA
era, whereas this rate has now decreased to 4-6 %.1-3
Accordingly, fewer patients are undergoing pelvic lymph
node dissection (PLND) and fewer lymph nodes have
been removed by PLND in recent times.4,5 Moreover,
the advent of minimal invasive surgery procedures has
also influenced the decision to perform PLND. Data
from the Surveillance Epidemiology and End Results
Kwang Hyun Kim has been awarded "Eminent Scientist of the Year 2014" of International Research Promotion Council. (www.irpc.org)
Correspondence: Koon Ho Rha, M.D., Ph.D., Department of Urology, Urological Science Institute, Yonsei University College of Medicine,
50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea.
Tel: 82-2-2228-2310, Fax: 82-2-312-2538, E-mail: [email protected]
87
Kwang Hyun Kim
(SEER) cancer registry reveals that PLND was five times
more likely to be performed on men treated with open
surgery compared with men treated with minimal invasive
surgery.6 However, the incidence of lymph node metastasis
has been reported to be 20-30% in patients with high
risk prostate cancer,7,8 and the presence of lymph node
metastasis still represents an adverse prognostic factor
for disease progression and survival, and portends poorer
outcomes.9,10
PLND is still the most accurate method for determining
nodal staging. However, PLND is associated with
increased morbidity and long operating times; moreover,
meticulous surgical technique is required in order for
PLND to be effective. Unfortunately, recent sophisticated
imaging procedures have shown limited success in
accurately identifying nodal involvement, and are limited
by their significant costs.11,12 Several nomograms have
been developed to better predict the risk of lymph node
metastasis,13-15 and some urologists perform PLND
based on such nomograms. However, the indication and
optimal extent of PLND treatment remains controversial.
Furthermore, no consistent conclusion has been reached
regarding the beneficial effects of PLND on survival in
patients with prostate cancer.
The aim of this review is to evaluate the role of PLND
in patients with prostate cancer by summarizing issues
from the current literature regarding PLND in prostate
cancer, including the indication, extent, and therapeutic
role of PLND.
Current Indication of Pelvic
Lymph Node Dissection
Even though PLND is the most accurate method for
determining lymph node metastasis, PLND is associated
with increased morbidity and complications. The benefits
of PLND must therefore be weighed against the potential
risk of PLND, and the decision to perform PLND is
usually based on the characteristics of prostate cancer.
Several nomograms have been created to evaluate the
risk of lymph node metastasis, using preoperatively
available parameters.13-17 However, nomograms should
be developed based on results from extended PLND
in order to better assess the actual risk of lymph node
metastasis. Predictive models based on limited PLND
are associated with a significant risk of underestimating
the risk of nodal metastasis. Thus, Godoy et al14 recently
updated their nomogram to include only patients who
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 13, No. 2, April 2014
underwent extended PLND, thereby demonstrating
improved calibration of their nomogram, along with a
high discriminative accuracy. Briganti et al13 also recently
published their updated nomogram, which was based
on their extended PLND series. The updated Briganti
nomogram was recently validated in a different European
cohort, and also demonstrated good performance
characteristics.18 However, the characteristics of study
cohorts affect the performance of predictive models, and
the predictive models developed in Western populations
might not be applicable in Asian populations.
We have recently developed a nomogram for predicting
lymph node metastasis in Asian men with prostate
cancer.15 We used data from 541 men who underwent
both RALP and PLND, performed by a single surgeon,
between 2008 and 2011. The median number of lymph
nodes removed was 17; 45 patients (8.3%) exhibited
lymph node metastasis. Our nomogram was developed
based on the preoperative PSA level, clinical stage, and
biopsy Gleason score. This model produced a receiver
operating characteristic curve of 0.88, and demonstrated
high accuracy in internal validations. We suggest that
a value of 4% probability for lymph node invasion is
an appropriate cutoff for pursuing PLND. Using our
model with a 4% cutoff value, approximately 60% of
patients would be spared PLND. Current guidelines
also recommend performing PLND based on preexisting
nomograms. For instance, the European Association of
Urology guidelines recommend performing PLND on
patients with a risk of lymph node metastasis greater than
5%, based on the Briganti nomogram.13,19 Similarly, the
National Comprehensive Cancer Network (NCCN) uses
the nomogram by Cagiannos et al16 and recommends
performing PLND on patients with predicted probabilities
of lymph node metastasis of 2% or more.20 However, the
nomogram used by Cagiannos et al16 originated from
a cohort of individuals who underwent limited PLND.
As mentioned above, limited PLND is associated with
a high rate of false-negative results regarding lymph
node invasion. Abdollah et al21 validated the NCCN
guideline nomograms in patients treated with extended
PLND, and demonstrated that the NCCN nomogram,
which was based on a limited PLND template, tends
to underestimate the true rate of lymph node invasion.
Therefore, this study concluded that the recommended
cutoff of 2% might not be appropriate to trigger PLND.
The diagnosis of lymph node metastasis with current
imaging modalities, such as computed tomography or
magnetic resonance imaging (MRI), has limited accuracy
in prostate cancer.22 These imaging modalities assess the
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Pelvic Lymph Node Dissection in Prostate Cancer: ....
presence of lymph node invasion based on size and shape.
Therefore, small metastases often remain undetectable,
and lymph nodes enlarged by reactive hyperplasia are
often misinterpreted as metastatic lesions.23 In prostate
cancer, only 30% of lymph node metastases were detected
by these imaging modalities, as the sizes of most metastatic
lymph nodes were less than 8 mm.22 Lymphotropic
ultrasmall superparamagnetic particles of iron oxide
(USPIO) can be used as an MRI contrast agent for the
detection of metastasis in normal-sized lymph nodes.
Meta-analysis has shown that USPIO-enhanced MRI
offers higher diagnostic performance than conventional
MRI.24 In prostate cancer, combining USPIO-diffusion
with weighted MRI was shown to improve the detection
of metastasis in normal-sized lymph nodes.25 Currently,
USPIO is not commercially available, and further research
into other iron nanoparticle-based approaches is needed.
Despite their improved diagnostic accuracies, the chance
of lymph node metastasis resulting in a negative finding
by USPIO MRI is 8-11%.25 Thus, negative USPIO MRI
results do not rule out the need for a PLND.
Extent of Pelvic Lymph Node
Dissection
The rate of lymph node metastasis increases linearly with
the extent of PLND.14,26 The ideal number of lymph
nodes removed has not yet been determined. While an
autopsy series suggested that at least 20 lymph nodes
should be removed for accurate staging,27 the probability
that a patient has been correctly staged as node negative
can be predicted based on not only the number of lymph
nodes removed, but also the pathologic characteristics
of the particular prostate cancer.28 However, meticulous
excision within an anatomical template is more important
than total lymph node count for defining an adequate
PLND. Current guidelines recommend PLND with an
extended template in patients with risk of lymph node
metastasis.19,20 However, the anatomical boundaries
of extended PLND vary among centers, and the
terminologies and definitions of extended PLND have not
been standardized. Generally, the template of extended
PLND includes at least the internal iliac region, in
addition to the obturator and external iliac areas.19,20,29
Many researchers have demonstrated that up to 50% of
all positive lymph nodes are found at the internal iliac
area.29-31 However, some authors include removal of
the presacral area,32,33 and other authors advocate the
additional removal of common iliac nodes, at least up to
the ureteric crossing, based on imaging studies.34,35
To define the primary landing lymphatic drainage
sites, Mattei et al34 used SPECT techniques, comprising
intraprostatic injection of technetium (Tc-99m)
nanocolloid, in 34 patients with organ-confined prostate
cancer. They demonstrated that only 63% of all primary
landing sites were located in a region including the
external iliac, obturator, and internal iliac vessels, and
proposed a new extended PLND template including the
common iliac area up to the ureter crossing. Application
of new PLND templates removed close to 75% of
all primary landing sites. A recent study examining
nodal metastasis using molecular techniques detected
considerable numbers of positive lymph nodes in the
common iliac area.35 Moreover, this study noted that the
common iliac area was the only positive region in 11% of
patients with nodal metastasis.
Regarding retroperitoneal lymph nodes, the level to
which the template should be extended is currently
unknown. In a prospective study of 19 very high risk
prostate cancer patients, PLND was performed with a
template including the retroperitoneal area up to the
aortic bifurcation.36 In very high risk patients, positive
retroperitoneal lymph nodes were found in 14 (77.8%)
patients, and no patients with negative common iliac
lymph nodes had positive retroperitoneal lymph nodes.
These results suggest that retroperitoneal lymph nodes
might not represent primary lymphatic landing sites, and
that the lymphatic spread ascends through common iliac
lymph nodes in prostate cancer.
The necessity of performing PLND in the presacral
area also has been controversial. Joniau et al32 used a
multimodality technique, encompassing SPECT and Tc99m nanocolloid approaches, for mapping pelvic lymph
node metastasis in prostate cancer patients. This study
included 74 patients at risk of lymph node metastasis
or clinical T3 tumors, and proposed a new template
including the presacral area. The authors emphasized
the importance of removing all metastatic lymph nodes.
By adding the presacral area to the template, the rate
of patients in whom all metastatic lymph nodes were
removed increased from 88% to 97% while the rate
of correctly staged patients increased from 94% to
97%. Nevertheless, the benefits of PLND must also be
balanced against the associated morbidity. Lymph node
dissection in presacral area is associated with injury to
the pelvic plexus, particularly the superior hypogastric
nerves, which form the superior hypogastric plexus at the
level of the sacral promontory. Injuries to these plexuses
may affect functional outcomes.37 In rectal cancer
literature, an association between the extent of lateral
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Kwang Hyun Kim
pelvic lymphadenectomy and functional outcome has
been demonstrated.38 Although the impact of PLND on
functional outcome has not been clearly demonstrated in
prostate cancer, surgeons should acknowledge the possible
adverse impact on functional outcome during dissection
of the presacral region.39,40
Therapeutic Role of Pelvic Lymph
Node Dissection
The therapeutic benefit of PLND has remained as
a contentious issue in the prostate cancer field. Many
researchers did not find improved oncologic outcomes
with extended PLND treatment, even in patients with
higher risk disease.41-44 On the other hand, some authors
have suggested that PLND may improve prostate cancer
outcomes by eliminating micrometastatic nodal disease
that might otherwise progress to systemic dissemination.
In a retrospective analysis of 4,611 patients, Masterson et
al45 reported that an increased number of removed lymph
nodes was significantly associated with biochemical-free
survival. The data obtained from 13,020 men in the
SEER program also revealed improved prostate cancerspecific survival in patients with increased numbers of
removed lymph nodes.46 While these improved oncologic
outcomes were obtained from patients without lymph node
involvement, Allaf et al47 reported that extended PLND
treatment improved biochemical-free survival in patients
with lymph node-positive disease. However, these results
were based on retrospective analyses and non-randomized
designs. In a non-randomized observational study, the
template of PLND is selected based on the features of the
particular cancer; thus, biases can occur in the analysis
of oncologic outcomes. Moreover, extended PLND
provides more accurate staging information, affecting the
pathological nodal staging. For example, patients with
lymph node metastasis diagnosed by extended PLND
may be classified as lymph node metastasis-free, if only
limited PLND is performed on them. This phenomenon is
a well-known statistical artifact known as the ‘Will Rogers
phenomenon’.48 Thus, extended PLND treatment might
result in improved oncologic outcomes, according to the
stage migration results. Multivariate analysis, adjusting
the status of lymph node involvement, would also not
completely overcome this artifact.
To overcome the limitations of retrospective analysis
and eliminate bias caused by stage migration, we utilized
propensity score matching to adjust for preoperative
variables associated with either lymph node metastasis or
the performance of PLND.26 Our analysis included 170
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 13, No. 2, April 2014
patients treated with extended PLND, and 294 patients
treated with limited PLND, for intermediate or high risk
prostate cancer. Propensity score matching placed 141
patients into each group, with no significant differences
between the groups regarding their clinicopathological
characteristics, except the incidence of lymph node
metastasis. Although we were unable to demonstrate
improved biochemical outcomes in the extended PLND
group, the hazard ratio trend was inverted in favor of
extended PLND (3 year biochemical-free survival rates,
77.8% and 73.5%, hazard ratio 0.85, p=0.497) in the
matched cohort. However, the median follow up period
was only 36 months; this period is too short to draw
meaningful conclusions regarding oncologic outcomes.
Thus, it would be extremely interesting to update our
cohort results at 5 or 7 years.
In addition, a large series of patients treated with
PLND has shown that a considerable subset of men with
lymph node metastasis remained free of disease at long
term follow up. Furthermore, their oncologic outcomes
were not necessarily poor. In a series of 122 patients
with lymph node metastasis, the median cancer-specific
survival at year 10 was 60.1%, and patients with 2 or less
positive nodes had favorable long term results.49 Another
large series of 703 node-positive patients also revealed
that patients with up to 2 positive nodes experienced
excellent cancer-specific survival rates, compared with
patients with more than 2 positive lymph nodes.50 A
recent study investigated the natural histories of 369
patients with lymph node metastasis, who were not
treated with routine adjuvant hormonal treatment.51
The overall and cancer-specific survival rates at year 10
were 60% and 72%, respectively. This study also found
significant differences in oncologic outcomes, according
to the extent of nodal invasion. Given the high rate of
cancer control and the different outcomes according to
their nodal metastatic burdens, we speculate that lymph
node-positive prostate cancers are not systemic diseases
in all cases; therefore, PLND might have a curative effect
in patients with minimal nodal invasion.
Recently, the first prospective randomized trial
examining the impact of the extent of PLND was
published from China. 52 This study included 360
patients, randomized to receive either extended PLND
or standard PLND. The median follow up time was 74
months; extended PLND was found to be associated with
improved biochemical outcomes in patients with both
intermediate and high risk prostate cancer. Although this
initial evidence is informative, cancer-specific survival
was not described in this study. Currently, randomized
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trials comparing extended versus limited PLND are
ongoing in Europe (NCT#01555086); these trials will
evaluate the impact of PLND on long term outcomes in
terms of both cancer-specific and overall survival rates.
Conclusions
In this review, we focused on the indication, extent,
and efficacy of PLND in treating prostate cancer. The
decision to perform PLND is based on a predictive
model. Currently, several nomograms are available, which
originated from an extended PLND series. Clinicians
should choose the nomogram derived from the population
which most closely resembles their patient population.
In patients with risk of lymph node metastasis, PLND
should be performed with an extended template. The
benefit from removing lymphatic tissue in the presacral
or common iliac area must be balanced against the
associated morbidity. Although the therapeutic benefit
of PLND has been debated, a growing body of evidence,
including a recent randomized controlled trial, indicates
that PLND is of therapeutic benefit.
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