european urology 55 (2009) 261–270
available at www.sciencedirect.com
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Platinum Priority – Prostate Cancer
Editorial by George N. Thalmann on pp. 271–272 of this issue
Two Positive Nodes Represent a Significant Cut-off Value for
Cancer Specific Survival in Patients with Node Positive Prostate
Cancer. A New Proposal Based on a Two-Institution Experience
on 703 Consecutive N+ Patients Treated with Radical
Prostatectomy, Extended Pelvic Lymph Node Dissection and
Adjuvant Therapy
Alberto Briganti a,*, Jeffrey R. Karnes c, Luigi Filippo Da Pozzo a, Cesare Cozzarini d,
Andrea Gallina a, Nazareno Suardi a, Marco Bianchi a, Massimo Freschi b, Claudio Doglioni b,
Ferruccio Fazio d, Patrizio Rigatti a, Francesco Montorsi a, Michael L. Blute c
a
Department of Urology, Vita-Salute University, Milan, Italy
Department of Pathology, Vita-Salute University, Milan, Italy
c
Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, Minnesota, USA
d
Department of Radiotherapy, Vita-Salute University, Milan, Italy
b
Article info
Abstract
Article history:
Accepted September 18, 2008
Published online ahead of
print on October 1, 2008
Background: Currently, the 2002 American Joint Committee on Cancer (AJCC)
staging system of prostate cancer does not include any stratification of
patients according to the number of positive nodes. However, node positive
(N+) patients share heterogeneous outcomes according to the extent of
lymph node invasion (LNI).
Objective: To test whether the accuracy of cancer specific survival (CSS)
predictions may be improved if node positive patients are stratified according to the number of positive nodes.
Design, Setting, and Participants: The study cohort included 703 N+ M0
patients treated with radical prostatectomy (RP) and extended pelvic lymph
node dissection (ePLND) between September 1988 and January 2003 at two
large Academic Institutions. Number of positive nodes was dichotomized
according to the most informative cut-off predicting CSS. Kaplan-Meier
curves assessed cancer specific survival rates. Predictive accuracy of the
current N stage and of the new N classification in predicting CSS was
quantified with Harrell’s concordance index after adjusting for pathological
(T) stage and internally validated with 200 boostraps resamples. Differences
in predictive accuracy were compared with the Mantel-Haentzel test.
Keywords:
Prostate cancer
Radical prostatectomy
Lymph node metastasis
Number of positive nodes
Please visit
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* Corresponding author. Department of Urology, Vita-Salute University, Via Olgettina 60,
20132 Milan, Italy. Tel. +39 02 26437286; Fax: +39 02 26437298.
E-mail address: [email protected], [email protected] (A. Briganti).
0302-2838/$ – see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2008.09.043
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european urology 55 (2009) 261–270
Results and Limitations: Mean follow-up was 113.7 months (median: 112.5,
range 3.5–243). The mean number of nodes removed was 13.9 (range: 2–52).
The mean number of positive nodes was 2.3 (range: 1–31). The most
informative cut-off of positive nodes in predicting CSS was 2. Of all, 532
(75.7%) patients had 2 or less positive nodes, while 171 (24.3%) had more
than 2 positive nodes. Patients with 2 or less positive nodes had significantly better CSS outcome at 15 year follow-up compared to patients with
more than 2 positive nodes (84% vs 62%; p < 0.001). After adjusting for
pathological stage, multivariable predictive accuracy of the new N staging
(2 or >2 positive nodes) was 65.0% vs 60.1% when the number of positive
nodes was not considered (4.9% gain; p < 0.001).
Conclusions: We demonstrated that patients with up to 2 positive nodes
experienced excellent CSS, which was significantly higher compared to
patients with more than 2 positive nodes. Moreover, a significant improvement in CSS prediction was reached when the number of positive nodes
was considered. Thus, our results reinforce the need for a stratification
of node positive patients according to the number of positive nodes and
may warrant consideration in the next revision of the pathologic TNM
classification.
# 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Radical prostatectomy (RP) is a commonly performed and effective treatment for patients with
organ confined prostate cancer [1]. Large clinical
series have demonstrated that RP represents also a
valid treatment option for patients with locally
advanced prostate cancer [2–8]. In this context, great
interest has been focused on patients with prostate
cancer and lymph node invasion (LNI). Although the
diagnosis of prostate cancer has shifted to early
clinical stages in the PSA era, nodal metastases are
indeed still diagnosed in a wide range of patients [9–
13]. Historically, patients with nodal metastases
were not considered surgical candidates and were
usually treated with hormonal therapy (HT) and/or
radiotherapy (RT). However, recent studies reported
excellent cancer specific outcomes of patients with
histologically proven nodal metastases submitted to
RP, with or without adjuvant HT [14–18].
Moreover, patients with LNI are not all at the
same risk of cancer recurrence and death. Indeed,
patients with a low volume of nodal disease have
significantly higher survival rates compared to
patients with higher volume of LNI, regardless of
adjuvant treatment administration [14–18]. Despite
these evidences, the 2002 American Joint Committee
on Cancer (AJCC) staging system of prostate cancer
does not include any stratification of patients
according to the number of nodes involved by
cancer [19]. This reflects the primary idea that node
positive prostate cancer is always a systemic disease
associated with overall long-term poor prognosis. In
contrast, a recent study has shown that patients
with a single nodal metastasis showed long-term
outcome as favourable as those without nodal
involvement [14]. Based on this data, we evaluated
the long term outcome in the largest node positive
(N+) prostate cancer series that has been published
to date. We stratified node positive patients undergoing RP, extended pelvic lymph node dissection
(ePLND) and adjuvant treatments according to the
extent of LNI. We hypothesized that the accuracy of
cancer specific survival (CSS) predictions may be
improved if node positive patients are stratified
according to the number of positive nodes.
2.
Materials and methods
Between September 1988 and January 2003, 703 consecutive
N+ M0 patients were treated with RP, ePLND and adjuvant
treatments at two large Academic Institutions. Pre-operative
staging included negative pelvic/abdominal computerized
tomography or ultrasound, bone scan and chest x-ray. All
patients underwent extended pelvic lymph node dissection
(including removal of obturator, external iliac and hypogastric
nodes) at the time of RP. All patients included in this study had
complete clinical and pathological data including age at
surgery, pre-operative PSA, pathological stage defined according to the 2002 AJCC staging system [19], pathological Gleason
score, surgical margin status, number of nodes removed as
well as number of positive nodes. Moreover, all patients
received adjuvant treatment, including hormonal blockade
alone or in combination with RT administered within 90 days
after RP. The decision to administer one or both adjuvant
treatments followed the surgeon and patient discussion about
possible treatment options. Medical hormone deprivation
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european urology 55 (2009) 261–270
and adjuvant RT. Furthermore, the accuracy of each mentioned variable for CSS prediction was assessed with the
Harrell’s concordance index. Two hundred bootstrap resamples were used to reduce overfit bias. Finally, the accuracy of
pathological T stage alone as well as of multivariable models
predicting CSS not accounting for the extent of LNI (based on
pre-operative PSA, pathological T stage, pathological Gleason
score, surgical margin status and adjuvant RT) was compared
to the predictive accuracy (PA) of multivariable models
including either the new N staging based on the number of
positive nodes or LND. The statistical significance in PA gain
induced by the inclusion of the number of positive nodes or
LND was assessed with the Mantel Haenszel test. All statistical
tests were performed with the use of S-PLUS Professional,
version 1 (MathSoft Inc, Seattle, WA, USA). All tests were twosided with a significance level at 0.05.
therapy was generally intended to be lifelong. However, given
the retrospective nature of this study, it is uncertain whether
patients discontinued treatment after a period of androgen
deprivation therapy.
Kaplan-Meier analysis was used to estimate BCR free
survival, overall survival (OS) and CSS rates at 5, 8, 10 and
15 years after surgery. Biochemical failure was defined as
2 consecutive PSA values >0.4 ng/ml. Cause of death was
identified from death certificates or physician correspondence. Number of positive nodes was dichotomized according
to the most informative cut-off predicting CSS. This was
obtained applying ANOVA test for every possible cut-off value
and choosing the lowest p-value. The log rank test was used to
compare CSS rates of patients sub-divided according to the
dichotomized number of positive nodes. Moreover, the
association between the number of positive nodes as well
as lymph node density (number of positive nodes over number
of total nodes removed [LND]) and CSS was tested in
univariable and multivariable Cox regression models after
accounting for pre-operative PSA, pathological stage, pathological Gleason score, surgical margin status, year of surgery
(namely, 1993–1997 vs 1988–1992 and 1998–2003 vs 1988–1992)
3.
Results
Clinical and pathological characteristics of patients
included in the study are shown in Table 1. Of the
Table 1 – Clinical characteristic of 703 patients with lymph node invasion (LNI) submitted to radical prostatectomy,
extended pelvic lymph node dissection and adjuvant therapy
Variables
All patients
(n = 703) No (%)
Patients treated at
Vita-Salute University,
Milan, Italy (n = 250) No (%)
Patients treated at
Mayo Clinic, Rochester,
Minnesota, US (n = 453) No (%)
Age
Mean (median)
Range
65 (66)
47–80
65.9 (66)
47–80
64.4 (65)
47–79
Pre-operative PSA
Mean (median)
Range
28.9 (17.2)
0.9–616
24.7 (15.6)
2.8–148
31.3 (17.9)
0.9–616
0.004
0.046
Pathological stage (TNM 2002)
pT2a/b/c
pT3a
pT3b
pT4
82
118
452
51
Pathological Gleason score
6 or less
7
8–10
148 (21.1)
347 (49.4)
208 (29.5)
53 (21.2)
114 (45.6)
83 (33.2)
95 (21)
233 (51.4)
125 (27.6)
Surgical margin status
Positive
Negative
444 (63.2)
259 (36.8)
154 (61.6)
96 (38.4)
290 (64)
163 (36)
Number of lymph nodes
removed and examined
Mean (median)
Range
Number of positive lymph nodes
Mean (median)
Range
p value
<0.001
(11.7)
(16.8)
(64.3)
(7.3)
21
39
151
39
(8.4)
(15.6)
(60.4)
(15.6)
61
79
301
12
(13.5)
(17.4)
(66.4)
(2.6)
0.24
0.56
<0.001
13.9 (13)
2–52
16.6 (15.5)
3–52
2.3 (1)
1–31
2.5 (1)
1–31
532 (75.7)
171 (24.3)
183 (73.2)
67 (26.8)
12.4 (12)
2–37
2.1 (1)
1–19
0.07
0.27
2
>2
Data are tabulated according to the treatment Institution.
PSA: Prostate Specific Antigen.
349 (77)
104 (23)
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european urology 55 (2009) 261–270
Table 2 – Clinical characteristic of 703 patients with lymph node invasion (LNI) submitted to radical prostatectomy,
extended pelvic lymph node dissection and adjuvant therapy
Variables
Adjuvant RT + HT
(n = 171) No (%)
Adjuvant HT
(n = 532) No (%)
Age
Mean (median)
Range
64.1 (64.5)
47–80
65.3 (66)
47–80
Pre-operative PSA
Mean (median)
Range
30.6 (19)
0.9–321
28.4 (16.2)
1.6–616
Pathological stage (TNM 2002)
pT2a/b/c
pT3a
pT3b
pT4
Pathological Gleason score
6 or less
7
8–10
Surgical margin status
Positive
Negative
Number of lymph nodes removed and examined
Mean (median)
Range
Number of positive lymph nodes
Mean (median)
Range
p value
0.06
0.55
<0.001
6
20
115
30
(3.5)
(11.7)
(67.3)
(17.5)
76
98
337
21
(14.3)
(18.4)
(63.3)
(3.9)
29 (17.0)
77 (45.0)
65 (38.0)
119 (22.4)
270 (50.8)
143 (26.8)
131 (76.6)
40 (23.4)
313 (58.8)
219 (41.2)
16.4 (15)
2–52
13.1 (12)
2–44
2.4 (2)
1–16
2.2 (1)
1–31
121 (70.8)
50 (29.2)
411 (77.3)
121 (22.7)
0.02
<0.001
<0.001
0.36
0.10
2
>2
Data are tabulated according to the type of adjuvant treatment administered.
RT: radiotherapy; HT: hormone therapy; PSA: Prostate Specific Antigen.
703 patients included, 453 (64.4%) were treated at
Mayo Clinic, Rochester, Minnesota, U.S., while the
remaining 250 (35.6%) were treated at Vita-Salute
University, Milan, Italy (Table 1). Significant differences in terms of mean age, pre-operative PSA,
pathological stage as well as number of lymph nodes
removed and examined were found between the
two treatment Institutions (all p 0.04; Table 1). All
patients received adjuvant treatments: 532 out of
703 (75.7%) received adjuvant HT alone, while the
remaining 171 (24.3%) received a combination of
adjuvant RT and HT. As shown in Table 2, patients
treated with adjuvant RT + HT had significantly
higher rate of locally advanced prostate cancer,
higher pathological Gleason score, higher rate of
positive surgical margins as well as higher mean
number of lymph nodes removed (all p 0.02).
Conversely no difference has been found between
the two groups in terms of mean age at surgery, preoperative PSA and number of positive nodes (all
p 0.06).
The most-informative positive lymph-node cutoff in predicting prostate CSS was 2 ( p < 0.001). Thus,
patients were divided into two groups according to
this cut-off: 2 positive nodes (n = 532; 75.7%) and
more than 2 positive nodes (n = 171; 24.3%). Interestingly, significant differences in terms of mean PSA,
pathological stage and Gleason score as well as
surgical margin status were found between the two
groups, in favour of patients with lower volume of
nodal disease (all p 0.04; Table 3). Moreover patients
with more than 2 positive nodes were significantly
younger and received a more extensive PLND at the
time of RP (all p < 0.001; Table 3).
Figs. 1–3 show Kaplan Meier curves assessing BCR
free survival, OS and CSS rates after surgery,
respectively. Mean follow-up was 113.7 months
(median: 112.5, range 3.5–243). Overall, 109 out of
703 (15.5%) patients died of prostate cancer, while
140 (19.9%) died of other causes.
Biochemical recurrence free-survival rate at 5, 8,10
and 15 years was 71, 62, 58 and 49%, respectively.
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european urology 55 (2009) 261–270
Table 3 – Clinical characteristic of 703 patients with lymph node invasion (LNI) submitted to radical prostatectomy,
extended pelvic lymph node dissection and adjuvant therapy
Variables
Patients with 2 positive
nodes (n = 532)
Patients with >2 positive
nodes (n = 171)
Age
Mean (median)
Range
65.5 (66)
48–80
63.4 (65)
47–79.3
Pre-operative PSA
Mean (median)
Range
27.1 (15.1)
0.9–616
34.6 (22.4)
2.9–248
<0.001
0.04
Pathological stage (2002 AJCC)
pT2a/b/c
pT3a
pT3b
pT4
73
95
330
34
Pathological Gleason score
6 or less
7
8–10
126 (23.7)
264 (49.6)
142 (26.7)
22 (12.9)
83 (48.5)
66 (38.6)
Surgical margin status
Positive
Negative
318 (59.8)
214 (40.2)
126 (73.7)
45 (26.3)
Number of lymph nodes
removed and examined
Mean (median)
Range
Number of positive lymph nodes
Mean (median)
Range
p value
0.004
(13.7)
(17.9)
(62.0)
(6.4)
9
23
122
17
(5.3)
(13.5)
(71.3)
(9.9)
0.001
0.001
<0.001
13.1 (12)
2–52
16.3 (16)
4–43
1.3 (1)
1–2
5.3 (4)
3–31
<0.001
Data are tabulated according to the number of positive nodes (2 vs 2 positive nodes).
PSA: Prostate Specific Antigen.
Overall survival rate at 5, 8,10 and 15 years was 84, 74,
67 and 49%, respectively. Cancer specific survival rate
at 5, 8,10 and 15 years was 90, 85, 82 and 78%,
respectively. Patients with 2 or less positive nodes
had significantly better CSS outcome at 15 year
follow-up compared to patients with more than 2
positive nodes (84% vs 62; p < 0.001; Fig. 4).
Table 4 shows the univariable and multivariable
Cox regression models predicting CSS. At univariable analysis, all variables, except for year at surgery
( p = 0.88), adjuvant RT ( p = 0.19) and pre-operative
PSA ( p = 0.18), were significantly associated with
CSS (all p values0.001). The number of positive
nodes dichotomized according to the most-infor-
Fig. 1 – Kaplan-Meier estimates of biochemical recurrence
(BCR) free survival after surgery in the entire population
(n = 703; dotted lines represent 95% confidence intervals).
Fig. 2 – Kaplan-Meier estimates of overall survival (OS) after
surgery in the entire population (n = 703; dotted lines
represent 95% confidence).
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european urology 55 (2009) 261–270
Fig. 3 – Kaplan-Meier estimates of cancer specific survival
(CSS) after surgery in the entire population (n = 703; dotted
lines represent 95% confidence).
mative cut-off was highly significantly associated
with CSS at univariable analysis ( p < 0.001). Interestingly, the number of positive nodes (2 vs >2
positive nodes) maintained a highly significant
association with CSS even at multivariable analyses
( p = 0.002), as well as pathological stage ( p = 0.03),
pathological Gleason score ( p < 0.001) and surgical
margin status ( p = 0.008). Patients with more than
2 positive nodes had a 1.9-fold higher risk of dying
for prostate cancer compared to patients with 2 or
less positive nodes after accounting for all the other
predictors. Of note, adjuvant RT reached a highly
independent predictor status for CSS prediction
( p = 0.002) at multivariable analysis. Similarly,
LND was highly significantly associated with CSS
at univariable and multivariable analyses (all
p < 0.001).
Finally, in the univariable PA analyses, the number
of positive nodes was the third most informative
predictor of CSS (PA: 60.3%), after pathological
Gleason score (PA:63.8%) and LND (61.8%; Table 3).
Moreover, when the variable accounting for the
number of positive nodes (2 vs >2 positive nodes)
was added to pathological stage, the multivariable PA
reached up to 65.0% and significantly exceeded that
of pathological T stage alone (65.0% vs 60.1%; 4.9%
gain; p < 0.001; Table 5). The inclusion of the new N
staging also significantly increased the PA of multivariable models based on PSA, pathological stage,
Gleason score, surgical margin status and adjuvant
RT (72.1% vs 69.9%, 2.2% gain, p < 0.001). Similarly,
when LND was included in multivariable models
predicting CSS significant increases in PA were
reached (all p < 0.001). However, the effect of LND
on CSS predictions was slightly inferior compared to
the new N staging based on the number of positive
nodes (Table 5).
4.
Discussion
The incidence of nodal metastases in patients
affected by prostate cancer and submitted to RP
has dramatically decreased in the PSA era [1].
Nevertheless, even in the most selected clinical
series, nodal metastases are still diagnosed in up to
40% of patients submitted to ePLND [11]. However,
although the presence of nodal metastases represents an adverse pathological characteristic, not all
patients with prostate cancer and LNI are at the
same risk of BCR ad cancer specific death [14–18].
Several trials have indeed shown that patients with
Fig. 4 – Kaplan-Meier estimates of cancer specific survival (CSS) after surgery according to the number of positive nodes (1 vs
2 positive nodes; log rank test: p = 0.29; =2 vs more than 2 positive nodes; log rank test: p < 0.001).
267
european urology 55 (2009) 261–270
Table 4 – Univariable and Multivariable Cox regression models predicting prostate cancer specific survival and
corresponding predictive accuracy.
Univariable
Analysis HR; p value
Multivariable Analysis
HR; p value
Multivariable
Analysis HR; p value
Univariable
Predictive Accuracy
Pathological stage (2002 AJCC)
T3a vs T2a/b/c
T3b vs T2a/b/c
T4 vs T2a/b/c
–; 0.001
2.0; 0.2
3.8; 0.01
7.1; 0.001
–; 0.03
1.3; 0.6
2.1; 0.1
4.0; 0.02
–; 0.06
1.4; 0.6
2.2; 0.14
3.7; 0.03
60.1%
New N staging
>2 vs 2 positive nodes
2.4; <0.001
1.9; 0.002
–;–
Pre-operative PSA
1.002; 0.18
1.0; 0.7
1.0; 0.6
58.5%
Pathological Gleason score
7 vs 2–6
8–10 vs 2–6
–; <0.001
2.4; 0.01
5.4; <0.001
–; <0.001
1.8; 0.09
3.9; <0.001
–; <0.001
1.8; 0.10
4.0; <0.001
63.8%
Surgical margin
status (positive vs negative)
2.4; <0.001
1.9; 0.008
1.7; 0.02
59.7%
Adjuvant RT
0.7; 0.19
0.42; 0.002
0.49; 0.01
54.8%
Year of surgery
1993–1997 vs 1988–1992
1998–2003 vs 1988–1992
–; 0.88
0.91; 0.66
0.89; 0.68
–; 0.7
0.8; 0.4
0.9; 0.87
–; 0.48
0.8; 0.23
0.8; 0.48
58.4%
Lymph node density
13.7; <0.001
–;–
6.3; <0.001
61.8%
60.3%
PSA: Prostate Specific Antigen; RT: radiotherapy; HR: hazard ratio.
Lymph node density: number of positive nodes over number of nodes removed.
Table 5 – Accuracy of models predicting prostate cancer specific survival
Pathological stage alone (2002 AJCC)
Pre-operative PSA + Pathological stage + Pathological
Gleason score + Surgical margin status + Adjuvant RT
Baseline
Predictive
Accuracy
Predictive accuracy
after inclusion of new N staging
(>2 vs 2 positive nodes)
60.1%
69.9%
65.0% (+4.9%^)
72.1% (+2.2%^)
Predictive accuracy
after the inclusion of
lymph node density
64.9% (+4.8%^)
71.9% (+2.0%^)
^Mantel Haenszel test after bootstraping: p < 0.001.
Lymph node density: number of positive nodes over number of nodes removed.
PSA: Prostate Specific Antigen; RT: radiotherapy.
low volume of lymph node metastases have significantly higher CSS rates compared to patients
with more extensive LNI [14–18]. Thus, the number
of positive nodes is key for determining patient
prognosis. Despite these evidences, the revised 2002
AJCC staging system for prostate cancer does not
provide any stratification of patients with nodal
metastases according to the number of positive
nodes. Patients are indeed classified as having (N1)
or not (N0) nodal metastases [19]. Conversely, the N
classification of the 1992 prostate cancer AJCC
staging system included a stratification of node
positive prostate cancer patients into two different
categories (N1 and N2) according to the number and
size of nodes involved by metastatic spread [20].
Therefore, the AJCC lymph node staging has been
simplified in 2002. However, these changes might
not translate into comparable CSS predictive
accuracies due to the different outcomes of node
positive patients according to the extent of LNI [14–
18].
Based on these controversies, we aimed at
quantifying the accuracy of the revised 2002 AJCC
staging system in predicting CSS of node positive
patients and to compare it with the accuracy of
multivariable models including the number of
positive nodes as a covariate. We performed our
analysis in the largest series of node positive
prostate cancer available (n = 703) treated with RP,
ePLND and adjuvant treatments. Patients were
sub-divided into two groups according to the
most-informative cut-off of positive nodes for CSS
prediction (namely, 2 vs >2 positive nodes).
Interestingly, we confirmed the overall excellent
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european urology 55 (2009) 261–270
cancer specific outcome of LNI patients. Prostate
CSS rate at 15 years was as high as 79%. Similarly,
about 50% of patients treated with a multimodal
approach were free of BCR at 15-year follow-up.
Moreover, we confirmed the key role represented by
the number of positive nodes in predicting CSS of
patients with LNI. Men with more than 2 positive
nodes had significantly less favourable cancer
characteristics at diagnosis (all p 0.04; Table 3)
and lower CSS rates at 15 year follow-up compared
to patients with 2 positive nodes (62% vs 84%,
respectively; p < 0.001; Fig. 4). This was confirmed by
univariable and multivariable Cox regression models, where patients with more than 2 positive nodes
had significantly lower CSS rates, even after
accounting for all other key CSS predictors (such
as pre-operative PSA, pathological stage and Gleason score, year of surgery, surgical margin status
and adjuvant RT). Patients with more than 2 positive
nodes had roughly a 2-fold higher risk of dying for
prostate cancer compared to patients with 2
positive nodes after accounting for the effect of all
the other mentioned predictors (Table 4).
Finally, we compared the predictive accuracy of
the 2002 AJCC staging system (not accounting for the
number of positive nodes) in predicting CSS with the
accuracy a two-variable model including both
pathological T stage and the number of positive
nodes (namely, 2 vs more than 2 positive nodes).
Interestingly a 4.9% gain in bootstrap-corrected PA
was reached when data on the number of positive
nodes was included into the model (65.0 vs 60.1%;
p < 0.001, Table 5). Significant gains in PA were
also reached when the number of positive nodes
was added to a multivariable post-operative
model ( p < 0.001, Table 5). Therefore, a significant
increase in the CSS predictive ability has been
reached when the number of positive nodes was
considered. Interestingly, despite a highly significant association with CSS, the effect of LND on CSS
predictions was slightly inferior compared to the
new N staging based on the number of positive
nodes (Table 5).
Several aspects of our study are noteworthy. First,
our results reinforce the need for stratification of
node positive prostate cancer patients according to
the number of positive nodes. Our results are in line
with previous studies supporting extremely favourable long term outcome of patients with low volume
of nodal disease compared to patients with more
extensive nodal invasion [14–18]. Bader et al [16]
reported a 78% cause specific survival rate in
patients treated with RP and ePLND and who did
not undergo any adjuvant therapy until progression.
Interestingly, among those with 1 positive node, 39%
remained free of clinical or biochemical progression,
compared to 12% of patients with 2 or more positive
nodes. Similar results have been reported by
Daneshmand et al [17] who assessed the long term
outcome of a large retrospective node positive series
treated with ePLND. Roughly 31% of patients
received adjuvant HT. The 10-year clinical recurrence-free survival rate was as high as 65%. When
stratified by positive lymph node density (LND),
patients with a LND of 20% or greater were at higher
risk for clinical recurrence compared to those with a
density of less than 20% (relative risk:2.31; p < 0.001).
Cheng et al [14] reported a 79% 10-year cause specific
survival in a large series of 322 patients treated by
RP and prolonged adjuvant HT. Interestingly, after
10 years, CSS rate was as high as 94% in patients
with a single node metastasis. This rate was not
significantly different from CSS of patients without
nodal involvement.
However, none of the previous studies assessed
the predictive ability of the number of positive
nodes for CSS prediction. Boorjan et al previously
found > 2 positive nodes to be an independent
predictor of outcome at multivariable analyses [18].
Similarly, Schumacher et al have recently reported
significantly higher 10-year CSS rates in patients
with 2 positive nodes compared to patients with
3 positive nodes not receiving any adjuvant
therapy (78.6 vs 33.4%, respectively) [21]. However,
this cut-off was arbitrarily used in both studies and
the increase in PA associated with the inclusion of
the number of positive nodes was not tested. Kattan
[22] indeed indicated that statistical significance is
not synonymous with predictive ability. A truly
informative variable should increase the combined
PA of base predictors, in addition to achieving
independent, multivariate predictor status. Therefore, we compared bootstrap-corrected PA of the
2002 TNM staging system with and without the
number of positive nodes as a predictor. Interestingly, the number of positive nodes was able to
significantly increase CSS predictions (gain:4.9%;
p < 0.001) when added to the base variable represented by pathological T stage. Therefore, we
consider patient classification according to number
of positive nodes a key variable for CSS predictions
of node positive patients.
Second, our results are based on the largest series
of node positive prostate cancer published to date
(n = 703) assessed at a long-term follow-up. Moreover, all our patients were treated with an anatomically defined extended pelvic lymph node
dissection in the PSA era, which avoids any bias
related to the diagnosis of LNI as well as to the
current applicability of our findings [23].
european urology 55 (2009) 261–270
Despite several elements of interest, our study is
not devoid of limitations. First, all patients included
in the analyses were submitted to adjuvant treatments after surgery. This may be criticized as a
confounder of the impact of RP and PLND alone on
lymph node positive prostate cancer. However, the
use of adjuvant HT reflects a practice that is not
uncommon among practicing urologists, based on
the evidence of improved overall survival, CSS and
progression-free survival of node positive prostate
cancer submitted to adjuvant HT [24]. However, it
has to be acknowledged that our results might not
applicable to node positive patients left untreated
after surgery until progression. Nevertheless, even
when adjuvant HT was not administered to node
positive patients, patients with low volume of nodal
burden had significantly better outcome compared
to patients with higher number of positive nodes
removed [15,16,21]. This may suggest a potential
curative role of PLND in selected category of
patients. However, such hypothesis cannot be
confirmed in our series since all patients received
adjuvant HT after surgery.
Second, the differences in the population characteristics between the two contributing Institutions
might represent another limitation of our study
(Table 1). However, the two cohorts did not differ in
terms of the extent of LNI (i.e. number of positive
nodes) which represented the key variable of our
study. Moreover, the effect of all these differences
was accounted for by including patient characteristics as covariates in multivariable models.
Third, our analysis was in part limited by the
differences in the way the lymph nodes were sent
for pathological assessment between the two contributing Institutions. Indeed, at Mayo Clinic lymph
nodes were submitted en bloc from each side of the
pelvis. Conversely, at Vita-Salute University lymph
nodes were submitted in multiple packages, which
has been shown to improve the quality of pathological assessment of the number of lymph nodes that
may be involved with metastatic cancer [25]. This
may be responsible for the difference in the mean
number of lymph nodes examined between the two
Centres. In addition, this may also be responsible
for the overall relatively low mean number of
lymph nodes examined in this series of extensive
nodal dissection (Table 1). Nevertheless, the mean
number of nodes removed was 13.9 which is
significantly higher compared to limited nodal
dissection series, where the mean number of nodes
removed was as low as 5.8 [26]. Moreover, the lack of
a central pathological re-assessment may represent
another important limitation. Indeed, pathological
269
evaluation of node specimens may account for
different number of nodes identified and examined.
For example, at some Institutions a more rigorous
search for lymph nodes within the surgical specimen may yield a higher number of nodes that are
submitted for microscopic examination, despite the
same number of lymph nodes removed. Indeed,
pathological specimen dissection based on tactile
findings may miss non-palpable lymph nodes,
especially when a large amount of fatty tissue
surrounds them. Thus, at pathological evaluation,
an LNI diagnostic bias may be introduced if size and
consistency are used as criteria for identification of
suspicious nodes.
5.
Conclusions
Our results based on 703 node positive prostate
cancer patients treated with RP, ePLND and adjuvant
treatments show favourable long-term outcome of
patients with LNI. We have demonstrated that the
number of positive nodes represents a key variable
for CSS predictions. Patients with up to 2 positive
nodes experience excellent CSS rate, which was
significantly higher compared to patients with more
than 2 positive nodes ( p < 0.001). Moreover, a
significant improvement in CSS prediction is
reached when the number of positive nodes is
considered ( p < 0.001). These results reinforce the
need for a stratification of node positive patients
according to the number of positive nodes and may
warrant consideration in the next revision of the
pathologic TNM classification.
Author contributions: Alberto Briganti 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: Briganti, Karnes, Blute, Montorsi.
Acquisition of data: Karnes, Gallina, Suardi, Bianchi, Briganti.
Analysis and interpretation of data: Briganti, Gallina, Suardi, Da
Pozzo, Karnes.
Drafting of the manuscript: Briganti, Karnes, Montorsi, Blute.
Critical revision of the manuscript for important intellectual content:
Rigatti, Montorsi, Cozzarini, Fazio, Briganti, Karnes, Blute, Da
Pozzo.
Statistical analysis: Briganti, Gallina.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: None.
Other (specify): None.
Financial disclosures: I certify that all conflicts of interest,
including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed
270
european urology 55 (2009) 261–270
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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