Fellows Institute
Cincinnati 2011
Sentinel lymph node controversies:
is this the end for ALND?
Hiram S. Cody III MD
Attending Surgeon
The Breast Service, Department of Surgery
Memorial Sloan-Kettering Cancer Center
Professor of Clinical Surgery
Weill Cornell Medical College
No disclosures
SLN biopsy works
SLN 2010
69 validation studies in 8059 patients
# pts
8059
SLN found
96%
SLN false-neg
Accuracy
(SLN-/AX+)
(SLN correct/total)
7%
97%
Kim T et.al. Cancer 2006;106:4-16
SLN 2010
Results of 5 randomized trials
Trial
# pts
SLN found
SLN falsenegative
Accuracy
EIO
532
99%
9%
97%
B-32
5611
97%
10%
97%
ALMANAC
836
96%
7%
98%
GIVOM
749
95%
17%
95%
SNAC
1088
94%
5%
98%
61-73% had SLN-only disease
NSABP B-32
Clinically Negative Axillary Nodes
(n=5,611)
Randomization
GROUP 2
SLNB
GROUP 1
SLNB  ALND
Will false-negative SLN
procedures affect survival?
Path. Pos.
SLN
Path. Neg.
SLN
ALND
No ALND
Krag, DN et.al. Lancet Oncology 2010;11:927-33
100
NSABP B-32
OS: SLN negative (8 yr results)
60
40
84.6% received systemic therapy
20
Trt
SNR+AD
SNR
N
1975
2011
Deaths
140
169
HR=1.20 p=0.117
0
% Surviving
80
* 300 deaths triggered the definitive analysis
* 309 reported as of 12/31/2009
Data as of December 31, 2009
0
2
4
6
8
Years After Entry
Krag, DN et.al. Lancet Oncology 2010;11:927-33
60
40
84.6% received systemic therapy
20
Trt
SNR+AD
SNR
N
1975
2011
Deaths
315
336 HR=1.05 p=0.542
0
% Disease-Free
80
100
NASBP B-32
DFS: SLN negative (8 yr results)
Data as of December 31, 2009
0
2
4
Years After Entry
6
8
Krag, DN et.al. Lancet Oncology 2010;11:927-33z
Milan/EIO trial: 10 yr results
561 patients
1998-1999
95 mo f/u
Veronesi U et.al. Ann Surg 2010;251:595-600
SLN 2010
False-negative = axillary LR
# pts
# axillary LR
(%)
median f/u
SLN-/no ALND
48 studies*
14,959
0.3%
34 mo
median time
to axillary
LR
20 mo
SLN-/no ALND
IEO RCT
167
1.2%
95 mo
81 mo
SLN+/no ALND
6 studies
583
0.5%
31 mo
22 mo
*all with >3 yrs followup
Van der Ploeg IMC et.al. EJSO 2008:34:1277-84
We’ve asked and answered
the easiest questions
SLN 2010
Where have we come and what’s next?
• definition
• case selection
• technique
– nuclear medicine
– surgery
– pathology
• non-axillary SLN?
• SLN and neoadjuvant?
• SLN micromets?
• results
– morbidity
– local control
– survival
• SLN+ : ALND?
SLN 2010
What is the SLN?
1) a blue node
2) a hot node
3) a palpable node
SLN 2010
Case selection
• SLN biopsy is indicated in almost every patient with a cN0
invasive breast cancer
• for DCIS?
– YES, selectively
• for inflammatory/locally advanced CA?
– NO, outside of clinical trials
SLN 2010
Louisville (99 surgeons)
method
SLN found
SLN false-negative
single-agent
(n=244)
86%
11.8%
dual-agent
(n=562)
90%
5.8%
McMasters et.al.,JCO 2000;18:2560-2566
SLN 2010
Finding the positive SLN (n=255)
Dye failure
Dye success
Isotope failure
---
11%
Isotope success
11%
78%
Cody HS et.al. Ann Surg Oncol 2001;8:13-19
SLN 2010
Declining marginal benefit of dye
(finding the positive SLN)
100%
80%
60%
40%
20%
0%
isotope success
dye-only success
1-500
501-1000
1001-1500
1501-2000
88%
12%
90%
10%
96%
4%
98%
2%
Derossis et.al.JACS 2001;193:473-8
SLN 2010
Learning curve: ALMANAC
35
30
25
%
20
False negatives
15
Failed localisations
10
5
0
1
2 to 10
11 to
20
21 to
30
31 to
40
Most failed and
false-neg results
occurred in the
first procedure!
Clarke DH. Ann Surg Oncol 2004;11:211S-15S
SLN 2010
Morbidity: early reports
Lymphedema
rates
SLNB
ALND
7 case series
2000-2005
(n=1903)
5%
(0-13%)
29%
(7-77%)
SLN 2010
Z0010 morbidity
• prospective observational study of SLN biopsy
• >5500 patients accrued 1999-2003
• at 6 months
– 8.6% axillary paresthesias (>90% mild)
– 3.8% decreased upper extremity ROM
– 6.9% lymphedema (>2 cm over non-operated side)
• lymphedema was predicted by
– increased BMI (p=0.0005)
– increased age (p=0.04)
Wilke LG et.al. Ann Surg Oncol (suppl) 2005;12:S27
SLN 2010
MSKCC morbidity
Lymphedema
at 5 yrs
SLNB alone
n=600
SLNB/ALND
n=336
Subjective
3%
27%
p<0.0001
Measured
(>2 cm change)
5%
16%
p<0.0001
McLaughlin SA et.al. JCO 2008:26:5213-26
SLN 2010
MKCC sensory morbidity
p < 0.001
Temple LK, Ann Surg Oncol 2002;9:654-62
There are still some areas of debate
SLN 2010
Non-axillary SLN: what to do?
SLN 2010
Internal mammary experience
Author
IMN
imaged
IMN
found
IMN
positive
IMN-only
positive
Van der Ent/2001
n=256
25%
16%
4%
1.2%
Estourgie/2003
n=691
22%
19%
3%
1.3%
Farrus/2004
n=120
17%
12%
1.6%
0
Leidenius/2006
n=984
14%
11%
1.8%
0.8%
Madsen//2007
n=506
22%
17%
4%
1%
Heuts/2009
n=1008
20%
14%
3%
0.9%
SLN 2010
Reoperative SLN biopsy
Non-axillary
drainage on
preoperative
lymphoscintigram
“First time”
SLN biopsy
Reoperative
SLN biopsy
6%
(313/5482)
30%
(19/63)
p<0.0001
Port ER et.al. Ann Surg Onc 2007;8:2209-14
SLN 2010
SLN is better after neoadjuvant
(my bias)
• fewer operations
• false-negative rate is probably not increased
• avoidance of ALND for patients with pathologic CR
• ACOSOG 1071 (PI J Boughey)
Sentinel node
SLN before vs after chemo: cN0
MDACC 1994-2007
T1-3, cN0
n=3746
SLN found
SLN false-negative
SLN before chemo
n=3171
98.7%
4.2% (23/542)
SLN after chemo
n=575
97.4%
5.9% (5/84)
(p=0.017)
(p=0.48)
Hunt KK et.al. Ann Surg 2009 epub.
SLN 2010
Intraoperative assessment
100
90
80
70
sensitivity:
60
method+/SLN+ 50
40
(%)
30
20
10
0
frozen
touch prep
smear
All cases
<=2 mm
>2 mm
Size of nodal metastasis
Brogi E et.al. Ann Surg Oncol 2005;12:173-80
SLN 2010
EIO study (RT-PCR)
• 293 SLN in 293 pts
• frozen section of entire SLN
– 50m intervals
– H&E (IHC selectively)
– 118 sections (40-258)/SLN
• intervening tissue
– half for RT-PCR
– half discarded
Viale G et.al. Ann Surg 2008;247:136-42
SLN 2010
Frozen vs RT-PCR
100
90
80
70
sensitivity:
60
method+/SLN+ 50
40
(%)
30
20
10
0
frozen
RT-PCR
All cases
<=2 mm
>2 mm
Size of nodal metastasis
Brogi E et.al. Ann Surg Oncol 2005;12:173-80
Viale G et.al. Ann Surg 2008;247:136-42
SLN 2010
MSKCC pathology protocol
H&E and IHC
50m
H&E and IHC
1 H&E and 1 IHC (cytokeratin AE1:AE3)
stained section from each of two levels 50m apart
Tan LK et.al. J Clin Oncol 2008; 26: 1803-9
P
r
o
p
t
i
n
D
s
e
a
F
r
0. 0.2 0.4 0.6 0.8 1.0
MSKCC micromet
studyeas
D
is
by Sta
0
DFS by method of staining
p<0.001
H&E-/IHCIHC+
H&E+
H &E, +
IH C
+
H &E, +
IH C
H &E, IH C
5
1 0
1 5
2 0
2 5
T im
e
(
Tan
LK et.al. JCO
2008;Ye
26: 1803-9
MSKCC micromet study
DFS by size of metastasis
pN0 (negative)
pN0i+ (<0.2 mm)
pN1mi (0.3-2.0 mm)
p<0.001
Tan LK et.al. JCO 2008;26:1803
Netherlands micromet study
DFS by size of metastasis
N0 vs N0i+ or N1mi
N0 vs N0i+, N0 vs N1mi
p<0.001
p<0.002
p<0.001
de Boer M et.al. NEJM 2009;361:653-63
www.mskcc.org/nomograms
Van Zee KJ. Ann Surg Oncol 2003;10:1140-51
Predicting non-SLN metastases
SLN+ (all pts)
SLN+ (mets <2 mm)
A comparison
of 9 models
by AUC curves
Coutant C et.al. JCO 2009;27:2800-08
SLN 2010
Selective ALND for SLN+
1960 patients
with positive SLN
Nomogram score
(median predicted
likelihood of residual
axillary disease)
Axillary local
recurrence
( at 26 mo)
SLN+/no ALND
(n=315)
15% of SLN+
10%
1.9%
SLN+/ALND
(n=1645)
85% of SLN+
37%
0.36%
p=0.004
Park J et.al. Ann Surg 2007;245:462-8
SLN 2010
Selective ALND for IHC+ SLN
Nomogram score
(predicted odds of
non-SLN disease)
Axillary local
recurrence
( at 6.4 yrs)
SLN+/no ALND
(n=76)
44% of SLN+
4.2%
0%
(63% chemo, 5% ax RT)
SLN+/ALND
(n=95)
56% of SLN+
8.1%
0%
(88% chemo, 2% ax RT)
171 patients
with IHC+ SLN
Pugliese MS. Ann Surg Oncol 2010;17:1063-68
SLN 2010
Fewer ALND for SLN+
(FS negative or not done)
80
75
p<0.001
70
% ALND
65
for
SLN+ 60
55
50
1997
1998
1999
2000
2001
2002
2003
2004
Year
Park J et.al. Ann Surg 2007;245:462-8
SLN 2010
Patterns of ALND (NCDB)
23% no ALND
55% no ALND
Bilomoria KY et.al. JCO 2009;27:2946-53
SLN 2010
Trends in ALND for SLN+ (NCDB)
SLN+ and
no ALND
%
Bilomoria KY et.al. JCO 2009;27:2946-53
SLN 2010
Outcome +/- ALND (NCDB)
Axillary local
recurrence
5 yr relative
survival
SLN micrometastases (<2 mm)
SLN only
0.4%
(n=802)
SLN/ALND
0.2%
(n=2357)
SLN macrometastases (>2 mm)
SLN only
1.0%
(n=5596)
SLN/ALND
1.1%
(n=22591)
99%
98%
90%
89%
Bilomoria KY et.al. JCO 2009;27:2946-53
2010
annus mirabilis!
1) micromets on IHC?
2) micromets on H&E?
3) ALND for SLN+?
ACOSOG Z0010-Z0011
Z0010
cN0 and BCT
SLN biopsy
Bone marrow aspiration
SLN+
Z0011
randomize to
ALND
clinician/patient
blinded to IHC
and bone marrow
SLNObserve
Observe
suspended 12/04 at n=889 due to
slow accrual and too few events
www.acosog.org
Z0010 trial
Survival by staining method
Method
H&E
negative
H&E
positive
IHC
negative
IHC
positive
(3945/5184)
(1239/5184)
(3595)
(350)
5 year
survival
95.6%
92.8%
95.8%
95.1%
(95% CI)
(95.0-96.3)
(91.3-94.3)
p=0.0002
(95.0-96.5)
(92.7-97.5)
p=0.53
Cote R et.al. ASCO 2010
NSABP B-32
Clinically Negative Axillary Nodes
(n=5,611)
Randomization
GROUP 2
SLNB *
GROUP 1
SLNB*  ALND
A combined 1390 pts
had H&E+ SLNs
with f/u in 1389 pts
Path. Pos.
SLN
Path. Neg.
SLN
ALND
No ALND
Julian TB et.al. SABCS 2010
NSABP Protocol B-32
1390 pts with H&E+ SLN
Variable
size of
metastasis
Category
# pts
micro (0.2-2 mm)
312
macro (>2 mm)
422
Unknown
626
Julian TB et.al. SABCS 2010
NSABP B-32
DFS by SLN status on H&E
100
% Disease free
80
60
40
Patients
Neg SN
Pos SN (Micromets)
Pos SN (Macromets)
20
HR* (95% CI)
P-value*
0.998 (0.765-1.302)
1.783 (1.480-2.150)
0.99
<0.001
0
0
1
2
3
4
5
Years after Randomization
* HR (95% CI) & p-value comparison with Neg SN
6
7
Julian TB et.al. SABCS 2010
8
NSABP B-32
OS by SLN status on H&E
100
% Alive
80
60
40
Patients
Neg SN
Pos SN (Micromets)
Pos SN (Macromets)
20
HR* (95% CI)
P-value*
0.788 (0.518-1.199)
2.387 (1.891-3.013)
0.27
<0.001
0
0
1
2
3
4
5
Years after Randomization
* HR (95% CI) & p-value comparison with Neg SN
6
7
Julian TB et.al. SABCS 2010
8
NSABP B-32
IHC study
• 5611 accrued
• 3989 (71%) pN0 by H&E
– 2 mm slices
– routine IHC prohibited
• 3887 (97%) path
• 3884 (99.9%) follow up
• 95 mo median f/u
• IHC sections at UVM
– 0.5 and 1.0 mm deeper
• 15.9% IHC+
– 11.1% ITC (N0i+)
– 4.4% micromets (N1mi)
– 0.4% macromets (N1)
Weaver DL et.al. NEJM 2011; epub 1/19/11
NSABP B-32
Survival by IHC status
5 year
survival
IHC negative
n=3268
IHC positive
n=616
p
OS
95.8%
94.6%
0.03
DFS
89.2%
86.4%
0.02
DDFS
92.5
89.7%
0.04
Weaver DL et.al. NEJM 2011; epub 1/19/11
NSABP B-32
Multivariate hazard ratios
Variable
Death
Any event
Distant disease
IHC
(+ vs -)
1.40
1.31
1.30
p=0.02
p=0.009
p=0.03
0.53
0.60
0.68
p<0.001
p<0.001
p=0.001
1.32
1.41
1.42
p=0.06
p<0.001
p=0.01
Hormonal rx
(+ vs -)
T size
(T2-3 vs T1)
Weaver DL et.al. NEJM 2011; epub 1/19/11
NSABP B-32
Site of first treatment failure
First
treatment
Failure
IHC-negative
IHC-positive
Local
All patients
n=3268
2.6%
no ALND
n=1660
2.6%
All patients
n=616
2.6%
no ALND
n=300
1.3%
Regional
0.4%
0.5%
1.1%
1.7%
Distant
2.9%
3.2%
3.7%
3.3%
Weaver DL et.al. NEJM 2011; epub 1/19/11
SLN 2010
Are we asking the wrong question?
We’ve been asking
We should be asking
• “which SLN+ patients
don’t need ALND?”
• “do any SLN+ patients
need ALND?”
SLN 2010
Z0010-Z0011 trials (ACOSOG)
Z0010
cN0 and BCT
SLN biopsy
Bone marrow aspiration
SLN+
Z0011
randomize to
ALND
clinician/patient
blinded to IHC
and bone marrow
SLNObserve
Observe
suspended 12/04 at n=889 due to
slow accrual and too few events
www.acosog.org
SLN 2010
Z0011 schema
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010
Z0011 eligibility
Eligible
Ineligible
• clinical T1-2N0 breast cancer
• Nodal RT
• H&E-detected SLN metastases
• IHC-detected SLN metastases
• lumpectomy + whole breast RT
• Matted nodes
• adjuvant systemic therapy by
choice
• 3 or more involved SN
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010
Z0011 systemic therapy
Systemic therapy
SLN+/ALND
SLN+/no ALND
chemo
58%
58%
hormonal
46%
47%
chemo and/or
hormonal
96%
97%
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010
Z0011 locoregional recurrence
Recurrence
@ 6.3 yrs
median follow-up
SLN+
ALND
(n=388)
SLN+
no ALND
(n=425)
local
3.6%
1.9%
regional node
0.5%
0.9%
local+regional
4.1%
2.8%
p=0.47
Additional positive nodes in 27% of ALND’s
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010
Z0011 overall survival
Giuliano AE et.al. JAMA 2011;305:569-75
SLN 2010
Z0011 survival
Survival
@ 6.3 yrs
median follow-up
SLN+
ALND
(n=388)
SLN+
no ALND
(n=425)
DFS
82.2%
83.8%
OS
91.9%
92.5%
Giuliano AE et.al. ASCO 2010
SLN 2010
Z0011 overall survival
• HR boundary for noninferiority = 1.3
• unadjusted HR 0.79
– 0.56-1.10
• adjusted HR 0.87
– 0.62-1.23
– adjusted for age, ER
Giuliano AE et.al. JAMA 2011;305:569-75
SLN 2010
AMAROS trial: first 2000 patients
Straver ME et.al. JCO 2010; 28:731-7
SLN 2010
AMAROS adjuvant rx
SLN+
ALND
n=300
SLN+
Axillary RT
n=266
endocrine rx
32%
30%
chemo rx
35%
39%
chemo+endocrine rx
47%
46%
breast/chest wall RT
86%
89%
Straver ME et.al. JCO 2010; 28:731-7
SLN 2010
Conclusions
• SLN metastases detected only by IHC are of marginal
significance
• this has significant implications for
–
–
–
–
pathologists
surgeons
medical oncologists
patients!
• should IHC staining of SLN be abandoned?
SLN 2010
Conclusions
• in the absence of extensive axillary disease, SLN+
patients having BCT/ RT may not need ALND
• this has significant implications for
•
•
•
•
preop axillary staging by ultrasound and FNA: unnecessary?
intraoperative SLN assessment by pathology: irrelevant?
prediction of non-SLN status by nomograms: obsolete?
return to OR for ALND: historical interest only?
SLN 2010
ALND: the end of an era?
• IF ALND for SLN+ patients
– does not change systemic therapy
– does not reduce local recurrence
– does not improve survival
• THEN ALND for SLN+ patients should be done
– to salvage local recurrence (a rare event)
– not to prevent it
SLN 2008
MINDACT trial
EORTC 10041 (BIG 3-04)
T1-3N0 breast cancer
n = 6000
Low/Low risk
hormonal RCT
Discordant risk
(low/high or high/low)
Rx based on 70 gene profile
1) 70 gene profile
2) Adjuvant! Online
High/High risk
chemo RCT
+/- hormonal RCT
Rx based on Adjuvant! Online
www.mindact.org