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