Management of the axilla post Z0011 - GBCCgbcc2016.gbcc.kr/GBCC2014/upload/PFile_01_19_PL02_Hiram S. Cody III...Management of the axilla post Z0011 ... • PBI is usually limited to

Management of the axilla post Z0011

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

Global Breast Cancer Conference 2015

4th International Breast Cancer Symposium

Plenary Lecture 2

Local control and survival are related

EBCTCG. Lancet 2005; 366: 2087-2106

2005 overview

>10% reduction in 5-year LR*

25276 women, 51% node positive Local recurrence Breast cancer mortality

* among 24 types of treatment comparisons

EBCTCG. Lancet 2005; 366: 2087-2106

2005 overview

<10% reduction in 5-year LR*

16804 women, 43% node postive Local recurrence Breast cancer mortality

* among 24 types of treatment comparisons

SLN biopsy works

Kim T et.al. Cancer 2006;106:4-16

SLN 2014

69 observational studies in 8059 patients

# pts

SLN found

SLN false-neg

(SLN-/AX+)

Accuracy

(SLN correct/total)

8059

96%

7%

97%

SLN 2014

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

Van der Ploeg IMC et.al. EJSO 2008:34:1277-84

SLN 2014

False-negative = axillary LR # pts # axillary LR

(%)

median f/u

SLN-/no ALND

48 series*

14,959 0.3% 3 yr

SLN-/no ALND

IEO (RCT)

167 1.2% 8 yr

SLN-/no ALND

B-32 (RCT)

2011 0.7% 8 yr

*all with >3 yrs followup

SLN 2014

Time course of axillary LR

• 48 studies

• 14,959 SLN-negative pts

• axillary LR in 67 (0.3%)

• 34 mo median f/u

van der Ploeg IMC, et.al. EJSO 2008;34:1277-84

* 300 deaths triggered the definitive analysis

* 309 reported as of 12/31/2009

Years After Entry

% S

urv

ivin

g

0 2 4 6 8

0

20

40

60

80

100

Trt N Deaths

SNR+AD 1975 140

SNR 2011 169 HR=1.20 p=0.117

Data as of December 31, 2009

84.6% received systemic therapy

NSABP B-32

OS: SLN negative (8 yr results)

Krag, DN et.al. Lancet Oncology 2010;11:927-33

Years After Entry

% D

isea

se-F

ree

0 2 4 6 8

0

20

40

60

80

100

Trt N Deaths

SNR+AD 1975 315

SNR 2011 336 HR=1.05 p=0.542

Data as of December 31, 2009

84.6% received systemic therapy

NASBP B-32

DFS: SLN negative (8 yr results)

Krag, DN et.al. Lancet Oncology 2010;11:927-33z

Do we still need IHC

to examine SLN?

Z0010 trial

Survival by staining method

Method

H&E

negative

(3945/5184)

H&E

positive

(1239/5184)

IHC

negative

(3595)

IHC

positive

(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

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% (-1.2%)

0.03

DFS

89.2%

86.4% (-2.8%)

0.02

DDFS

92.5

89.7% (-2.8%)

0.04

Weaver DL et.al. NEJM 2011; epub 1/19/11

90% of patients received systemic therapy

(40% chemo, 68% hormonal)

Should ALND be routine for SLN+?

SLN 2014

Use of ALND (NCDB 1998-2005)

Bilimoria KY et.al. JCO 2009;27:2946-53

23% no ALND 36% no ALND

SLN 2014

Trends in ALND (NCDB 1998-2005)


SLN+ and

no ALND

%

SLN 2014

Outcome +/- ALND (NCDB) Axillary local

recurrence

5 yr relative

survival

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%


SLN 2014

SLN micromet/no ALND

(26 publications)

2001-2010

# pts

BCT

follow-up

axillary

LR

TOTAL

3395

44-100%

42 mo

0.3% (10)

Francissen CMTP et.al. Ann Surg Oncol 2012;19:4140-49

IBCSG 23-01

IBCSG trial 23-01

SLN micromet/no ALND

• cN0, T1-2, SLN micromets (<2 mm)

• randomize to ALND (n=464) vs no ALND (n=467)

– 95% had 1 SLN+

– 91% had BCT (98% with RT)

– additional positive nodes in 13% of ALND

•

• median f/u 5 yrs

Galimberti V et.al. Lancet Oncol 2013;14:297-305

IBCSG trial 23-01

SLN micromet/no ALND Event ALND

n=464

No ALND

n=467

Local 2% 2%

Regional 0.2% 1%

Distant 7% 5%

Death 4% 4%

Galimberti V et.al. Lancet Oncol 2013;14:297-305

SLN 2014

SLN macromet/no ALND

(16 publications)

2003-2010

16 studies

# pts

BCT

follow-up

axillary

LR

TOTAL

3268

29-100%

43 mo

0.7% (24)

Francissen CMTP et.al. Ann Surg Oncol 2012;19:4140-49

ACOSOG Z0011

www.acosog.org

Z0010-Z0011 trials (ACOSOG)

suspended 12/04 at n=889 due to

slow accrual and too few events

SLNB

Z0011

SLN+

ALND Observation

Z0010

SLN-

Observation

SLN 2014

Z0011 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 2014

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 2014

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

Giuliano AE et.al. Ann Surg 2010;252:439 Additional positive nodes in 27% of ALND’s

SLN 2014

Z0011 overall survival

Giuliano AE et.al. JAMA 2011;305:569-75

SLN 2014

Z0011 audit

Radiation field design SLNB arm

n=124

SLNB+ALND arm

n=104

Tangents only 83% 79%

Proportion high tangents* 53% 50%

Supraclavicular field 17% 21%

Posterior axillary boost 10% 6%

*sufficient records to determine field height Jagsi R et.al. JCO epub Aug 18, 2014

SLN 2014

Z0011 use of axillary RT

# nodes positive (#pts)

SLNB arm

SLNB+ALND arm

1 (n=140)

11% 7%

2 (n=44)

24% 16%

3 (n=9)

100% 33%

>4 (n=16)

100% 79%

Jagsi R et.al. JCO epub Aug 18, 2014

SLN 2014

Current MSKCC algorithm

• preop axillary US only for high risk patients

– cT3-4

– cN1-2

• no IHC staining for SLN

• For patients who meet Z0011 entry criteria

– no intraoperative frozen section

– no ALND for <2 SLN+

SLN 2014

MSKCC

post-Z0011

algorithm

Dengel LT et.al. Ann Surg Oncol 2014;21:22-27

ALND avoided for 84%

of Z0011-eligible patients

SLN 2014

Z0011 for non-Z0011 patients?

• can the policy of “SLN+/no ALND” be extended

to patients outside the Z0011 criteria?

– Mastectomy without RT?

– Partial breast RT?

– Neoadjuvant chemotherapy?

Z0011 for mastectomy?

SLN 2014

SLN+/no ALND (NCDB 1998-2000)

Axillary LR

at 5 yrs

SLN macromet

no ALND

(5596)

SLN micromet

no ALND

(802)

All SLN+

no ALND

(6398)

LR %

1%

0.4%

0.9%

LR #

56

3

59


MSKCC

SLN+/no axillary rx

• MSKCC 1997-2009

– 210 mastectomy

– 325 BCT

• SLN+

• no axillary-specific rx

• median f/u 58 months

Milgrom S et.al. Ann Surg Oncol 2012;19:3762

MSKCC

SLN+/no axillary rx 1997-2009 Mastectomy

(n=210)

BCT

(n=325)

Follow-up 4 yrs 5 yrs

Age 55 59

T1 69% 85%

T2 31% 15%

N0i+ 54% 58%

N1mi 37% 35%

N1 9% 7%

Nomogram score 9% 8%


MSKCC

SLN+/no axillary rx


All patients

MSKCC

SLN+/no axillary rx


Excludes pN0i+

Z0011 for partial breast RT?

PBI

The issues

• SLN negative/no ALND: axillary LR <<1%

• SLN positive/no ALND: axillary LR <1%

• Were the good results in Z0011 due to WBRT?

• If so, is PBI really safe?

PBI

some caveats

• PBI is usually limited to node-negative cancers

• axillae staged by SLNB and/or ALND

• “first event “ reporting underestimates event rates

SLN 2014

PBI trials

follow up

node neg.

Ax LR #

Ax LR %

Mammosite

registry

n=1449

59 mo

97%

10

0.79%

TARGIT

RCT

n=1113

60 mo

83%

4

0.35%

Ann Surg Oncol 2011; 18: 3415

Lancet 2013; 383: 603-613

Z0011 for neoadjuvant?

SLN biopsy

after neoadjuvant chemo

Systematic review of

27 studies

2148 patients*

2000-2009

SLN found SLN false negative

(SLN-/axilla+)

90.5%

(88-92)

10.5%

(8-14)

*23 single center, 4 multicenter:

1) Neoadjuvant chemo

2) SLN biopsy

3) Backup ALND

van Deurzen CHN et.al. Eur J Cancer 2009;45:3124-30

SLN biopsy

after neoadjuvant chemo Success rate False-negative rate

2000

2009

van Deurzen CHN et.al. Eur J Cancer 2009;45:3124-30

SLN biopsy

NSABP B-27 vs B-32

# pts

SLN found

SLN false-neg

B-27*

SLN biopsy

after chemo

428

89%

10.7%

B-32**

SLN biopsy

upfront

720

97%

9.7%

*JCO 2005;23:2694-2702 ** Lancet Oncol 2007;8:881-8

ACOSOG Z1071

SLN 2014

ACOSOG Z1071

• 708 pts (2009-2011) with cT0-4, N1-2, M0 disease

• all had neoadjuvant chemo, then SLNB/ALND

• SLN identified 92.5%

• pathologic CR 40%

Boughey JC et.al. JAMA 2013; online 10/7/13

SLN 2014

ACOSOG 1071

• False negative rate by # of SLN removed

– 1 SLN 31.5%

– 2 SLN 21%

– >2 SLN 12.6%

– >3 SLN 9.1%

• False negative rate by mapping technique

– Dye or isotope alone 20.3%

– Dye plus isotope 10.8%

Boughey JC et.al. JAMA 2013; online 10/7/13

SENTINA trial

SENTINA trial

prospective cohort study (n=1737)

• cN0: SLNB before chemo

– Arm A: SLN-, no further axillary surgery

– Arm B: SLN+, chemo, then re-SLNB/ALND

• if cN1-2: SLNB after chemo

– Arm C: if converted to cN0, SLNB/ALND

– Arm D: if still cN1-2, ALND

Bauerfeind KT et.al. SABCS 2012: Abstract S2-2

SENTINA trial

Outcome

1737 pts

103 institutions

Arms A+B

cN0

SLNB upfront

n=1022

Arm B

cN0/SLN+

SLNB upfront

chemo

re-SLNB/ALND

n=360

Arm C

cN1-2

Chemo upfront

SLNB/ALND

n=592

Success

(SLN found)

99%

61%

80%

False negative

(SLN-/axilla+)

-

52%

14%

Bauerfeind KT et.al. SABCS 2012: Abstract S2-2

SLN 2014

Two new neoadjuvant RCTs

N+

NAC

Post-NAC

SLN-

Nodal RT No RT

Post-NAC

SLN+

ALND

Nodal RT

No ALND

Nodal RT

NSABP B-51

RTOG 1304 Alliance 11202

Z0011 for non-Z0011?

Conclusions

• SLN+/no ALND is feasible for selected low-risk patients

outside the Z0011 selection criteria

• present evidence for mastectomy and PBI is insufficient

– low event rates but little data

– RCTs of “Z0011 for mastectomy, PBI” will be difficult

– prospective well-characterized cohort studies may be

informative

Z0011 for non-Z0011?

Conclusions

• present evidence for SLNB post-NAC is sufficient

– Success rate somewhat lower than SLNB in general

– False negative rate comparable to SLNB in general

– Technique matters

• Remove >2 SLN

• Map with dye + isotope

AMAROS trial

Name of presenter

Function of presenter

Radiotherapy or surgery of the axilla after

a positive sentinel node in breast cancer

patients: final analysis of the EORTC

AMAROS trial

By the EORTC Breast Cancer Group and

Radiation Oncology Group

In collaboration with the Dutch BOOG Group

and ALMANAC Trialists’ Group

Emiel J.T. Rutgers

The Netherlands Cancer Institute, Amsterdam

Clinical trial information: NCT00014612

Trial design

cT1-2

N0

R

SNB

Stratification: institution

Adjuvant systemic therapy by choice

ALND

AxRT

AxSN+

AxSN-

5-years axillary recurrence rate:

ALND 0.43% (4 / 744 events (0.54%))

AxRT 1.19% (7 / 681 events (1.03%))

<< hypothesis (2%)

Consequence: planned comparison is underpowered

Axillary recurrence rate

Axillary recurrence rate SN-

5-years axillary recurrence rate:

0.72% (25/3131 events (0.80%))

Lymphedema: clinical observation

P < 0.0001 P = 0.0027

27.8%

22.5% 23.2%

15.1% 13.8%

10.8%

%

P < 0.0001

Years after randomization

0

5

10

15

20

25

30

1 3 5

ALND

AxRT

Shoulder function

Results:

No significant differences in all 4 excursions

Trend towards impaired movement after AxRT in first year only

Years after randomization

Multivariate ANOVA: p =

0.29

Relative movement:

Excursion treated arm

Excursion untreated arm

Results:

Trend towards more difficulties to move

the arm after ART

Trend towards more swelling after

ALND

Quality of Life

AxRT ALND

AxRT ALND

Local control and biologic subtype

Local recurrence post BCT

Non-TN vs TN

RR, 0.49

95% CI, 0.33-0.73

p = .0005

Lowery AJ, Br Ca Res Treat 2012;133:831

n = 7174

Local recurrence post mastectomy

Non-TN vs TN

Lowery AJ, Br Ca Res Treat 2012;133:831

n = 5418

RR, 0.66

95% CI, 0.53-0.83

p = .0003

Locoregional recurrence by subtype

T1mic, T1a, T1b

Cancello G, Br Can Res Treat 2011;127:713

Gene signatures and LR

21 Gene Recurrence Score 70 Gene Signature

MP High Risk n = 492

MP Low Risk n = 561

p < 0.0001

Unpublished, courtesy of E Rutgers Mamounas EP, J Clin Oncol 2010; 28:1677

Local control and systemic therapy

Systemic rx and LRR

declining proportion LRR over time

• 53 RCT’s

• 86,598 patients

• 1990-2011

• No interaction with

– Mastectomy vs BCT

– Adjuvant RT

– Menopausal status

Bouganim N et.al. Breast Cancer Res Treat 2013;139:603-606

Systemic rx and LRR

declining proportion LRR by rx

Bouganim N et.al. Breast Cancer Res Treat 2013;139:603-606

Systemic therapy reduces LR

EBCTCG Overview

EBCTCG, Lancet 2005;366:2087

Systemic Therapy RR of LR

Tam x5 yrs vs placebo 0.47

Chemotherapy vs none

(CMF or anthracyclines)

age < 50 0.63

age 50-69 0.70

Better systemic therapy

reduces LR more

Mannino M, Radiother Oncol 2009;90:14

Systemic Therapy RR of LR

Tam x5 yrs vs placebo 0.47

Anastrozole vs Tam 0.83

Letrozole vs Tam 0.70

Tam x2 Anastrozole vs Tam x5 0.50

Tam x5 Letrozole x5 vs Tam x5 0.63

Treatments that improve DFS + OS produce

a corresponding decrease in LR

Effect of systemic therapy on LR

independent of surgery type

Kiess AP, Cancer 2012;118:1982 Lanning R, ASCO Breast 2013

Memorial Sloan-Kettering Cancer Center

No trastuzumab

n = 70

3yr LRR: 7%

Dx 2002-4

Dx 2002-4

p = 0.01

Trastuzumab

n = 102

3yr LRR: 1%

T1-T2 N0, HER2+

BCS + RT

Dx 2002-2008

Dx 2005-8

p = 0.04

Dx prior 2005 Dx 2005-2007

T1-T3, N0, N+

MRM ± RT

Dx 1999-2007

No trastuzumab

n = 256

5yr LRR: 6.6%

Trastuzumab

n = 139

5yr LRR: 1.5%

Systemic therapy and LR

NSABP Trials

Anderson SJ, J Clin Oncol 2009;27:2466

Study ER Status n 10 yr IBTR (%)

B 13 - 116 3.5

B 14 + 530 3.6

B 19 - 389 6.5

B 20 + 1027 4.7

B 23 - 1084 4.3

Axillary management in breast cancer

Conclusions I

• SLN biopsy is well established BUT

– next-generation trials in cN0 breast cancer will

compare SLNB vs no axillary staging

– next-generation trials in cN+ breast cancer will

compare combinations of ALND and RT


Conclusions II

• The role of ALND for the prevention of axillary LR is in

decline

• ALND remains an option

– for treatment of gross axillary disease

– for salvage of axillary recurrence (an infrequent event)


Conclusions III

• For SLN+ patients, axillary RT appears equivalent to

ALND in locoregional control, with fewer side effects

and better QOL


Conclusions IV

• Locoregional control is a function of

– Disease burden

– Tumor biology

– Treatment (surgery, RT, and systemic)

• Our hope is that continued improvements in systemic

therapy will allow increasing conservatism in the use of

surgery and RT

Documents

Management of the axilla post Z0011 - GBCCgbcc2016.gbcc.kr/GBCC2014/upload/PFile_01_19_PL02_Hiram S. Cody III...Management of the axilla post Z0011 ... • PBI is usually limited to