lymph node dissection: what really counts? - … · lymph node dissection: what really counts? ......
TRANSCRIPT
Department of Urology
University Medical Center
Johannes Gutenberg University
Mainz, Germany
Joachim W. Thüroff
Lymph Node Dissection:
what really counts?
Lymph Node Dissection (LND)
• Techniques and extent
• Risks
• Staging effect
• Therapeutic effect of LND ?
- Excision of N+ lymph nodes
- Adjuvant therapy effect
Surgical Lymph Node Yield
• Technique and extent of dissection
• Completeness of dissection:
- Modifiers (e.g. nerve-sparing)
- Problem zones (pararectal,
behind internal & common iliac vessels)
Pathological Lymph Node Yield
• LN submission: En-bloc vs. separate packets
• Histological processing:
Defatting, sections/node, immunohistochemistry
• Pathological parameters:
Number of N+ / N0, size of N+,
extranodular extension, molecular parameters
• Sentinel node: first landing site
• Lymph node sampling: suspicious nodes
• Systematic lymph node dissection:
- Landing sites: primary / secondary
- Templates: groups / regions / levels
Techniques of Lymph Node Dissection
Liedberg F et al., J Urol 175: 84-89, 2006
• 81% of N+ tumors had positive SN
• 19% of N+ tumors had negative SN
(false negative SN)
Alternative lymphatic drainage
when regular drainage is blocked
by lymph node metastases
• 87% sentinel node identification
Techniques: SN in Metastatic Cases
Systematic Lymph Node Dissection
Wuppertal 1987 Mainz 1997
Mapping Study: Super-Extended LND
Leissner J et al, J Urol 171: 139-44, 2004
n = 290
Prospective study, Mainz
# LNs (11 - 99) 43
pN+ 28%
Renal arteries
Inf. mes. artery
Aortic bifurcation
Iliac bifurcation
Limited pelvic LND
( True pelvis )
Extended pelvic LND
Inferior
retroperitoneal LND
Complete
retroperitoneal LND
20 LN
10 LN
10 LN
10 LN
Level I
Level II
Level III
Level IV
Systematic Lymph Node Dissection
Drainage of Unilateral Tumors
• No correlation between sites
of tumor and of positive nodes
• Ipsilateral and contralateral
lymphatic landing sites
Complex lymphatic drainage
vs. metastases from previous
bladder tumor sites
Systematic, extended LND
Leissner J et al, J Urol 171: 139-44, 2004
• OR time
Complications of LND
• Risk of vascular damage
• Risk of nerve damage
- sexual dysfunction
- motoric lesions
- sensoric lesions
• Lymphocele formation
Effects of Lymph Node Dissection
• Staging effect
• Stage migration effect
• Will Rogers phenomenon
• Adjuvant therapy effect
• Therapeutic effect of LND ?
Dhar N et al., J Urol 179: 873-8, 2008
Tumor stage Template Patients N+
all patients N+ %
pT2 limited 15
200 7,5 %
pT2 extended 24
150 16 %
pT3 limited 29
136 21 %
pT3 extended 59
172 34 %
Staging Effect of LND
Capitanio U et al, BJUI 103: 1359-62, 2009
n = 731
Retrospective study
LNs (1-80) 19
pN+ 24%
75%
90%
25 LNs 45 LNs
Staging Effect of LND
25 LNs detect
75 % of pN+ cases
45 LNs detect
90 % of pN+ cases
Stage Migration through Extended LND
N0 N1 N2
20% 10%
N0 N1 N2 N0 N1 N2
70%
20%
10%
50%
30%
20%
Stage shift to the right (higher N-stages)
through detection of more positive nodes
10
20
30
40
50
60
70
Limited LND Extended LND
extending LND
Autopsy
Extended
LND
Limited
LND
Stage Migration through Extended LND
1/3: N+
N+micro N+macro
2/3: N0
N0
2/3: N0
N0
1/6: N+
N+macro
5/6: N0
N0 N+micro
1/3: N+
N+micro N+macro
June 20, 1985
THE WILL ROGERS PHENOMENON
Stage migration and new diagnostic techniques as a source of misleading statistics for
survival in cancer
Alvan R. Feinstein, Daniel M. Sosin, and Carolyn K. Wells
Feinstein AR et al, N Engl J Med 312: 1604-8, 1985
• Cancer survival statistics
• Retrospective comparison of oncological outcomes
• New diagnostic techniques
• Improved staging Stage migration
• Improved individual subset outcomes
• Unchanged survival rates of unaltered cohorts !
„When the Okies left Oklahoma and moved
to California, they increased
the average intelligence level
in both states“
Will Rogers, 1879 - 1935
American comedian
June 20, 1985
THE WILL ROGERS PHENOMENON
Stage migration and new diagnostic techniques as a source of misleading statistics for
survival in cancer
Alvan R. Feinstein, Daniel M. Sosin, and Carolyn K. Wells
Will Rogers Phenomenon
small large average size
of animals
average size
of animals
small large
Will Rogers Phenomenon
small large average size
of animals
Will Rogers Phenomenon
2/6
Survival
50
60
80
Autopsy Limited LND Extended LND
70
0
10
20
30
40
80%
N0
2/3
50%
1/6
N+
micro.
74%
5/6
N0
(& N+ micro.)
20%
1/6
N+
macro.
mean:65% mean:65%
20%
1/6
macro.
N+
80%
N0
2/3
mean:65%
35%
N+
1/3
(macro. &
micro.)
„Will Rogers Phenomenon“
Stage Migration ↔ Survival
Survival
0
10
20
30
40
50
60
80
Limited LND Extended LND
70
1/6
80%
N0
2/3
35%
1/3
(macro. &
micro.)
N+
74%
5/6
(& N+ micro.)
N0
mean:65%
„Will Rogers Phenomenon“
20%
1/6
macro.
N+
Stage Migration ↔ Survival
mean:65%
pT1-4 pN0-2 Limited LND
Extended LND pT1-4 pN0-2
Therapeutic
effect on survival
Subset Survival Analysis is not Permitted
in Retrospective Comparisons !
Therapeutic Effect of Extended LND ?
X X
Feinstein AR et al, N Engl J Med 312: 1604-8, 1985
• Direct therapeutic effect:
Excision of cancerous lymph nodes
• Indirect therapeutic effect:
More adjuvant therapies because of
increased detection of N+ stages
Therapeutic Effects of Extended LND
Meticulous PND Makes a Difference
Skinner DG, J Urol 128: 34-6, 1982
n = 153 pN+: 25%
Retrospective study
„PND can cure some patients with bladder
cancer metastatic to a few pelvic nodes“
# pN+ Survival
1-2 44%
3-5 50%
6-9 25%
>10 0%
Retrospective study (SEER)
No. of LN
removed
Mortality
Risk (HR)
p value
None 1.00
1-3 0.93 0.6602
4-6 0.52 0.0006
7-9 0.57 0.0021
10-14 0.38 <0.0001
15-19 0.57 0.0059
≥20 0.48 0.0017
BCA: Mortality ↔ Number of LN n = 1923
Konety et al, J Urol 169: 964-50, 2003
CS mortality when ≥4 LNs are removed
Poulsen et al, J Urol 160: 2015-20, 1998
BCA: Standard ↔ Extended LND n = 194
Retrospective study, Herlev
iliac bifurcation
14 LN (5-30)
aortic bifurcation
25 LN (9-67)
22% pN+ 28% pN+
standard LND ↔ extended LND
pT all, pN all
5-y. RFS
62%
56%
Poulsen et al, J Urol 160: 2015-20, 1998
n = 194
No survival benefit for extended LND
BCA: Standard ↔ Extended LND
≤ pT3a pN0
Survival benefit for extended LND in subsets ≤ pT3a
Poulsen et al, J Urol 160: 2015-20, 1998
n = 194
≤ pT3a pN all
5-y.RFS
85%
64%
5-y. RFS
90%
71%
BCA: Standard ↔ Extended LND
pT all pN all
5-y. RFS 62 vs 56%
n = 658
Retrospective study (pT2 and pT3 only)
12 LN (2-31) 22 LN (10-43)
13% pN+ 26% pN+
limited LND ↔ extended LND
Cleveland Clinic Bern
Dhar N et al, J Urol 179: 873 - 8, 2008
BCA: Limited ↔ Extended LND
RFS (pT3): p<0.0001
Dhar N et al, J Urol 179: 873 - 8, 2008
n = 658
Cleveland Clinic (limited LND)
Survival benefit for extended LN in
pT3 subset
BCA: Limited ↔ Extended LND
Bern (extended LND)
Abol Enein H et al, Eur Urol 60: 572-7, 2011
n = 400
BCA: Standard ↔ Extended LND
Prospective study
Survival benefit for extended LND
Abol Enein H et al, Eur Urol 60: 572-7, 2011
n = 400
BCA: Standard ↔ Extended LND
Prospective study
Survival benefit for extended LND in subset pN0
35 Tilki D et al., Eur Urol 64: 266-76, 2013
Systematic Review: Extent of LND
“Conclusions: Many consistent and concordant
observations, although of low level of evidence,
document that the extent of lymphadenectomy may
influence disease-free survival after RC independent
of the status of LNs and the pathologic stage of BCa.”
36
• Better with LND ↔ without LND (7 / 7 studies)
• Better with super- / extended LND ↔ limited / standard LND
(7 / 14 studies, at least one subset of patients Will Rogers?)
• Same with super-extended LND ↔ extended LND
• Awaiting 2 prospective randomized studies:
LEA study, SWOG 1011 study
Bruins HM et al., Eur Urol 166: 1065-77, 2014
n = 23 Studies n = 19.703 Patients
Oncological Outcomes:
Systematic Review: Extent of LND
37 Bi HL et al., BJUI 113: E39-48, 2014
n = 6 Studies n = 2824 Patients
RFS: pN all
p < 0.001
.
Survival benefit for extended LND
Metaanalysis: Extent of LND
38 Bi HL et al., BJUI 113: E39-48, 2014
n = 6 Studies n = 2824 Patients
RFS: ≤ pT2 RFS: pT3-4
p < 0.001 p = 0.81
. .
Survival benefit for extended LND only in
pT3-4 subset
Metaanalysis: Extent of LND
Systematic Reviews, Metaanalysis
……“of low level of evidence,“
Tilki D et al., Eur Urol 64: 266-76, 2013
Bruins HM et al., Eur Urol 166: 1065-77, 2014
Bi HL et al., BJUI 113: E39-48, 2014
……”the quality of the data was poor,”
……“the level of evidence of included studies was generally low.”
„Prospective randomized trials designed to define the optimal template of
lymphadenectomy and its impact on oncologic outcome are advocated.”
“It is hoped that data from ongoing randomized
clinical trials will clarify remaining uncertainties.”
“Two randomized controlled trials on ePLND vs non-ePLND are
awaited which should provide more clinically meaningful results.“
Limited versus Extended PLND
in Patients with BCA Undergoing RCx :
Survival Results from a Prospective, Randomized Trial
Gschwend J et al., ASCO 2016
LEA Study - AUO AB 25 / 02
n = 375
2 / 2006 - 8 / 2010
16 High volume hospitals in Germany
• Recurrence free survival (RFS)
• Cancer specific survival (CSS)
LEA Study - AUO AB 25 / 02
• Survival with extended LND: 7.3% (RFS) / 11.3% (CSS)
• Trend, not statistically significant (p = 0.28 / p = 0.13)
Gschwend J et al., ASCO 2016
n = 375
No. of
nodes
5 year
RFS
p
5 year
CSS
p
Limited
(n = 191)
19
62%
66.2%
Extended
(n = 184)
32
69.3%
0.28
77.5%
0.13
Extended Lymph Node Dissection in BCA
• Improved staging:
Detection rate of pN+ cases
• Improved patient selection::
Adjuvant systemic therapy
• Improved survival
?
Take Home - Messages
