Sentinel lymph node controversies:is this the end for ALND?
Hiram S. Cody III MDAttending Surgeon
The Breast Service, Department of SurgeryMemorial Sloan-Kettering Cancer Center
Professor of Clinical SurgeryWeill Cornell Medical College
Fellows InstituteCincinnati 2011
No disclosures
SLN biopsy works
Kim T et.al. Cancer 2006;106:4-16
SLN 201069 validation studies in 8059 patients
# pts SLN found SLN false-neg
(SLN-/AX+)
Accuracy(SLN correct/total)
8059 96% 7% 97%
SLN 2010Results of 5 randomized trials
Trial # pts SLN found SLN false-negative
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
No ALNDNo ALND
Clinically Negative Axillary NodesClinically Negative Axillary Nodes(n=5,611)(n=5,611)
NSABP B-32
GROUP 1GROUP 1SLNB SLNB ALND ALND
ALNDALND
Path. Neg.Path. Neg.SLNSLN
GROUP 2GROUP 2SLNBSLNB
RandomizationRandomization
Path. Pos.Path. Pos.SLNSLN
Krag, DN et.al. Lancet Oncology 2010;11:927-33
Will false-negative SLN procedures affect survival?
* * 300 deaths triggered the definitive analysis300 deaths triggered the definitive analysis** 309 reported as of 12/31/2009309 reported as of 12/31/2009
Years After EntryYears After Entry
% S
urv
ivin
g%
Su
rviv
ing
00 22 44 66 88
002020
40406060
808010
010
0
TrtTrt NN DeathsDeathsSNR+ADSNR+AD 1975 1975 140 140SNR SNR 2011 2011 169 HR=1.20 p=0.117 169 HR=1.20 p=0.117
Data as of December 31, 2009Data as of December 31, 2009
84.6% received systemic therapy
NSABP B-32OS: SLN negative (8 yr results)
Krag, DN et.al. Lancet Oncology 2010;11:927-33
Years After EntryYears After Entry
% D
isea
se-F
ree
% D
isea
se-F
ree
00 22 44 66 88
002020
40406060
808010
010
0
TrtTrt NN DeathsDeathsSNR+ADSNR+AD 19751975 315315SNR SNR 20112011 336 HR=1.05 p=0.542336 HR=1.05 p=0.542
Data as of December 31, 2009Data as of December 31, 2009
84.6% received systemic therapy
NASBP B-32DFS: SLN negative (8 yr results)
Krag, DN et.al. Lancet Oncology 2010;11:927-33z
Milan/EIO trial: 10 yr results
Veronesi U et.al. Ann Surg 2010;251:595-600
561 patients1998-199995 mo f/u
Van der Ploeg IMC et.al. EJSO 2008:34:1277-84
SLN 2010False-negative = axillary LR
# pts # axillary LR
(%)
median f/u median time to axillary
LR
SLN-/no ALND
48 studies*
14,959 0.3% 34 mo 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
We’ve asked and answered the easiest questions
SLN 2010Where have we come and what’s next?
• definition• case selection• technique
– nuclear medicine
– surgery
– pathology
• results– morbidity
– local control
– survival
• non-axillary SLN?
• SLN and neoadjuvant?
• SLN micromets?
• SLN+ : ALND?
SLN 2010What is the SLN?
1) a blue node
2) a hot node
3) a palpable node
SLN 2010Case 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
McMasters et.al.,JCO 2000;18:2560-2566
SLN 2010Louisville (99 surgeons)
method SLN found SLN false-negative
single-agent(n=244)
86% 11.8%
dual-agent(n=562)
90% 5.8%
Cody HS et.al. Ann Surg Oncol 2001;8:13-19
SLN 2010Finding the positive SLN (n=255)
Dye failure Dye success
Isotope failure --- 11%
Isotope success 11% 78%
Derossis et.al.JACS 2001;193:473-8
SLN 2010Declining marginal benefit of dye
(finding the positive SLN)
0%
20%
40%
60%
80%
100%
isotope success 88% 90% 96% 98%
dye-only success 12% 10% 4% 2%
1-500 501-1000 1001-1500 1501-2000
Clarke DH. Ann Surg Oncol 2004;11:211S-15S
SLN 2010Learning curve: ALMANAC
0
5
10
15
20
25
30
35
1 2 to 10 11 to20
21 to30
31 to40
% False negatives
Failed localisations
Most failed andfalse-neg resultsoccurred in the first procedure!
SLN 2010Morbidity: early reports
Lymphedema rates
SLNB ALND
7 case series2000-2005(n=1903)
5% (0-13%)
29% (7-77%)
Wilke LG et.al. Ann Surg Oncol (suppl) 2005;12:S27
SLN 2010Z0010 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)
SLN 2010MSKCC morbidity
Lymphedemaat 5 yrs
SLNB alonen=600
SLNB/ALNDn=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
Temple LK, Ann Surg Oncol 2002;9:654-62
SLN 2010MKCC sensory morbidity
p < 0.001
There are still some areas of debate
SLN 2010Non-axillary SLN: what to do?
SLN 2010Internal 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%
Port ER et.al. Ann Surg Onc 2007;8:2209-14
SLN 2010Reoperative SLN biopsy
“First time”
SLN biopsy
Reoperative
SLN biopsy
Non-axillary
drainage on
preoperative
lymphoscintigram
6%
(313/5482)
30%
(19/63)
p<0.0001
SLN 2010SLN 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 nodeSLN before vs after chemo: cN0
MDACC 1994-2007T1-3, cN0
n=3746SLN found SLN false-negative
SLN before chemon=3171
98.7% 4.2% (23/542)
SLN after chemon=575
97.4%
(p=0.017)
5.9% (5/84)
(p=0.48)
Hunt KK et.al. Ann Surg 2009 epub.
Brogi E et.al. Ann Surg Oncol 2005;12:173-80
SLN 2010Intraoperative assessment
0102030405060708090
100
sensitivity:method+/SLN+
(%)
All cases <=2 mm >2 mm
Size of nodal metastasis
frozentouch prepsmear
Viale G et.al. Ann Surg 2008;247:136-42
SLN 2010EIO study (RT-PCR)
• 293 SLN in 293 pts
• frozen section of entire SLN– 50 intervals
– H&E (IHC selectively)
– 118 sections (40-258)/SLN
• intervening tissue– half for RT-PCR
– half discarded
Brogi E et.al. Ann Surg Oncol 2005;12:173-80
SLN 2010 Frozen vs RT-PCR
0102030405060708090
100
sensitivity:method+/SLN+
(%)
All cases <=2 mm >2 mm
Size of nodal metastasis
frozenRT-PCR
Viale G et.al. Ann Surg 2008;247:136-42
Tan LK et.al. J Clin Oncol 2008; 26: 1803-9
SLN 2010MSKCC pathology protocol
50H&E and IHCH&E and IHC
H&E and IHCH&E and IHC
1 H&E and 1 IHC (cytokeratin AE1:AE3) stained section from each of two levels 50 apart
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25
Disease-Free Survival Curve by Staining
Time (Years)
Pro
po
rtio
n D
ise
ase
-Fre
e
- H&E, + IHC+ H&E, + IHC- H&E, - IHC
H&E-/IHC-
IHC+
H&E+
p<0.001
Tan LK et.al. JCO 2008; 26: 1803-9
MSKCC micromet study
DFS by method of staining
MSKCC micromet studyDFS 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 studyDFS by size of metastasis
de Boer M et.al. NEJM 2009;361:653-63
N0 vs N0i+ or N1mi N0 vs N0i+, N0 vs N1mi
p<0.001
p<0.001p<0.002
www.mskcc.org/nomograms
Van Zee KJ. Ann Surg Oncol 2003;10:1140-51
Predicting non-SLN metastases
Coutant C et.al. JCO 2009;27:2800-08
A comparison of 9 models
by AUC curves
SLN+ (all pts) SLN+ (mets <2 mm)
Park J et.al. Ann Surg 2007;245:462-8
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
Pugliese MS. Ann Surg Oncol 2010;17:1063-68
SLN 2010Selective ALND for IHC+ SLN
171 patients
with 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)
Park J et.al. Ann Surg 2007;245:462-8
SLN 2010Fewer ALND for SLN+
(FS negative or not done)
50
55
60
65
70
75
80
% ALNDfor
SLN+
1997 1998 1999 2000 2001 2002 2003 2004
Year
p<0.001
SLN 2010Patterns of ALND (NCDB)
Bilomoria KY et.al. JCO 2009;27:2946-53
23% no ALND 55% no ALND
SLN 2010Trends in ALND for SLN+ (NCDB)
Bilomoria KY et.al. JCO 2009;27:2946-53
SLN+ and no ALND
%
SLN 2010Outcome +/- ALND (NCDB)
Axillary local recurrence
5 yr relativesurvival
SLN micrometastases (<2 mm)
SLN only(n=802)
0.4% 99%
SLN/ALND(n=2357)
0.2% 98%
SLN macrometastases (>2 mm)
SLN only(n=5596)
1.0% 90%
SLN/ALND (n=22591)
1.1% 89%
Bilomoria KY et.al. JCO 2009;27:2946-53
2010annus mirabilis!
1) micromets on IHC?2) micromets on H&E?3) ALND for SLN+?
www.acosog.org
ACOSOG Z0010-Z0011
Z0010cN0 and BCTSLN biopsy
Bone marrow aspiration
SLN+Z0011
randomize to
SLN-Observe
ALND Observe
clinician/patientblinded to IHCand bone marrow
suspended 12/04 at n=889 due to slow accrual and too few events
Z0010 trialSurvival by staining method
Method H&Enegative
(3945/5184)
H&Epositive
(1239/5184)
IHCnegative
(3595)
IHCpositive
(350)
5 year survival(95% CI)
95.6%
(95.0-96.3)
92.8%
(91.3-94.3)p=0.0002
95.8%
(95.0-96.5)
95.1%
(92.7-97.5)p=0.53
Cote R et.al. ASCO 2010
No ALNDNo ALND
Clinically Negative Axillary NodesClinically Negative Axillary Nodes(n=5,611)(n=5,611)
NSABP B-32
GROUP 1GROUP 1SLNB* SLNB* ALND ALND
ALNDALND
Path. Neg.Path. Neg.SLNSLN
GROUP 2GROUP 2SLNB *SLNB *
RandomizationRandomization
Path. Pos.Path. Pos.SLNSLNA combined 1390 pts A combined 1390 pts
had H&E+ SLNshad H&E+ SLNswith f/u in 1389 ptswith f/u in 1389 pts
Julian TB et.al. SABCS 2010
NSABP Protocol B-32 1390 pts with H&E+ SLN
Variable Category # pts
size of metastasis
micro (0.2-2 mm) 312
macro (>2 mm) 422
Unknown 626
Julian TB et.al. SABCS 2010
NSABP B-32DFS by SLN status on H&E
Patients HR* (95% CI) P-value*Neg SNPos SN (Micromets) 0.998 (0.765-1.302) 0.99Pos SN (Macromets) 1.783 (1.480-2.150) <0.001
* HR (95% CI) & p-value comparison with Neg SN
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8Years after Randomization
% D
ise
as
e f
ree
Julian TB et.al. SABCS 2010
NSABP B-32OS by SLN status on H&E
Patients HR* (95% CI) P-value*Neg SNPos SN (Micromets) 0.788 (0.518-1.199) 0.27 Pos SN (Macromets) 2.387 (1.891-3.013) <0.001
* HR (95% CI) & p-value comparison with Neg SN
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8Years after Randomization
% A
liv
e
Julian TB et.al. SABCS 2010
NSABP B-32IHC 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-32Survival by IHC status
5 year survival
IHC negativen=3268
IHC positiven=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-32Multivariate hazard ratios
Variable Death Any event Distant disease
IHC(+ vs -)
1.40p=0.02
1.31p=0.009
1.30p=0.03
Hormonal rx(+ vs -)
0.53p<0.001
0.60p<0.001
0.68p=0.001
T size (T2-3 vs T1)
1.32 p=0.06
1.41p<0.001
1.42p=0.01
Weaver DL et.al. NEJM 2011; epub 1/19/11
NSABP B-32Site of first treatment failure
First treatment
Failure
IHC-negative IHC-positive
All patientsn=3268
no ALNDn=1660
All patientsn=616
no ALNDn=300
Local 2.6% 2.6% 2.6% 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 2010Are we asking the wrong question?
We’ve been asking
• “which SLN+ patients don’t need ALND?”
We should be asking
• “do any SLN+ patients need ALND?”
www.acosog.org
SLN 2010Z0010-Z0011 trials (ACOSOG)
Z0010cN0 and BCTSLN biopsy
Bone marrow aspiration
SLN+Z0011
randomize to
SLN-Observe
ALND Observe
clinician/patientblinded to IHCand bone marrow
suspended 12/04 at n=889 due to slow accrual and too few events
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010SLN 2010Z0011 schemaZ0011 schema
SLN 2010Z0011 eligibility
Eligible
• clinical T1-2N0 breast cancer
• H&E-detected SLN metastases
• lumpectomy + whole breast RT
• adjuvant systemic therapy by choice
Ineligible
• Nodal RT
• IHC-detected SLN metastases
• Matted nodes
• 3 or more involved SN
Giuliano AE et.al. Ann Surg 2010;252:439
SLN 2010Z0011 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 2010Z0011 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
Giuliano AE et.al. Ann Surg 2010;252:439Additional positive nodes in 27% of ALND’s
SLN 2010Z0011 overall survival
Giuliano AE et.al. JAMA 2011;305:569-75
SLN 2010Z0011 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 2010Z0011 overall survival
• HR boundary for non-inferiority = 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 2010AMAROS trial: first 2000 patients
Straver ME et.al. JCO 2010; 28:731-7
SLN 2010 AMAROS adjuvant rx
SLN+ ALNDn=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 2010Conclusions
• 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 2010Conclusions
• 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 2010ALND: 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
www.mindact.org
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)
High/High risk
chemo RCT
+/- hormonal RCT
1) 70 gene profile
2) Adjuvant! Online
Rx based on 70 gene profile Rx based on Adjuvant! Online