Monica Morrow MD!"#$%&'()$*+,'-.)/$)0'-$)1#2$

344$'(.)4$,,'5#46%7")'!"*#)'7%'!8#4#2*8'942787/0

:$;7)#*8'-87*4<=$,,$)#4/'!*42$)'!$4,$)

>?,"'@4,$)4*,#74*8'!74/)$++'74',"$'A.,.)$'7%'()$*+,'!*42$)!7)74*67&'!3

:$;7)#*8'-87*4<=$,,$)#4/'!*42$)'!$4,$)>BCD'E7)F'31$4.$&'G$H'E7)F&'GE'>??ID

Implications of ACOSOG Z11

for Clinical Practice:

Surgical Perspective

6 August 2011

Staging

Local Control

Survival

Why Do Axillary Dissection?

Fisher B, NEJM 2002;347:567

Nodal Treatment and Survival

NSABP B04

Women with Negative Nodes

Women with Positive Nodes

Years of Follow-up

Rela

pse-f

ree S

urv

ival (%

)

100

80

60

40

20

0

0 5 10 15 20 25

Pro

Smaller cancers, lower nodal disease burden

# nodes NOT deciding factor for systemic Rx.

Most patients get RT and systemic Rx.

Molecular determinants of prognosis, predictors

of treatment benefit available

Con

Local therapy does influence survival.

Revisiting Axillary Dissection for

SN Positive Patients

ACOSOG Z0011

A randomized trial of axillary node

dissection in women with clinical

T1-2 N0 M0 breast cancer who have a

positive SN

Principal Investigator: Armando E. Giuliano, MD

165 Investigators / 177 Institutions

Giuliano A, JAMA 2011;305:589

Inclusion/Exclusion Criteria

Eligibility

• Clinical T1 T2 N0

breast cancer

• H&E-detected

metastases in SN

(AJCC 5th edition)

• Lumpectomy with

whole breast

irradiation

• Adjuvant systemic

therapy by choice

Ineligibility

• Third field (nodal),

irradiation

• Metastases in SN

detected by IHC only

• Matted nodes

• 3 or more involved

SN

Z0011 Study Design Schema

Patient and Tumor Characteristics

Intent-to-treat

ALND

n = 420

SLND

n = 436

Median age 56 (24-92) 54 (25-90)

Clinical T1 68% 71%

ER+ 83% 83%

PR+ 68% 70%

LVI present 41% 36%

Patient and Tumor Characteristics

Intent-to-treat

ALND

n = 420

SLND

n = 436

Grade

1 22% 26%

2 49% 47%

3 29% 28%

Histology

Ductal 83% 84%

Lobular 7% 9%

Other 11% 8%

Giuliano A, Ann Surg 2010;252:426

SLNDALND

Adjuvant Systemic Therapy

Chemotherapy 57.9% 58.0%

Hormonal therapy 46.4% 46.6%

Either/Both 96.0% 97.0%

P = N.S.

Giuliano ASA Z0011 040810 11

Median Number of

Lymph Nodes Removed

106 (27.4%) of patients treated with ALND

had additional positive nodes removed beyond SN.

Giuliano ASA Z0011 040810 13

Number of Positive Lymph Nodes

Intent-to-Treat Analysis

Locoregional Recurrence Z11

Giuliano A, Ann Surg 2010;252:426

ALND

n = 420

SN

n = 436

Local 15 (3.6%) 8 (1.8%)

Regional 2 (0.5%) 4 (0.9%)

Total 17 (4.1%) 12 (2.8%)

p = 0.11

Median F/u 6.3 yrs

Survival Outcomes Z11

Median F/u 6.3 yrs

Giuliano A, JAMA 2011;305:589

% DFS % OS

SN 83.9 (80.2-87.9%) 92.5 (90-95.1%)

ALND 82.2 (78.3-86.3%) 91.8 (89.1-94.5%)

HR 0.82 (0.58-1.17) 0.79 (.56-1.1)

Adjusted HR* 0.88 (0.62-1.25) 0.87 (.62-1.2)

Adjusted for age, adjuvant rx

Z11: Is it Practice Changing?

Yes, but not for:

• Clinically N+

• LABC

• Mastectomy

• PBI

• Neoadjuvant Therapy

5. Follow-up isn’t long enough

4. Not enough ER negatives

3. Not enough young women

2. “Failed Study” — didn’t reach accrual goal

Top 5 Things Critics Don’t Like

About Z11

Time to Nodal Relapse

Author Local Rx % ER+

Axillary

Recurrence

Median Time

Fisher, B04 Mastectomy ? 14.8 mo

Greco BCT 75 30.6 mo

Martelli BCT 92 33 mo

Fisher B, NEJM 2002;347:567

Greco M, Ann Surg 2000;232:1

Martelli G, Ann Surg Oncol 2011;18:125-33

Multivariate Analysis

of Regional Nodal Failure

Nodal Factors Tumor Factors Rx Factors

# Excised T size Nodal RT

# Positive LVI Chemotherapy

% Positive ER status

ECE Margin status Patient Factors

Metastasis size Age

Grills IS, IJROBP 2003;56:658

n = 1500

Rx: BCT, Axillary Dissection ± Nodal RT

Maximum size nodal mets only significant predictor

of regional recurrence.

Median F/u 8.1 yrs

Age and Z11

Regional Recurrence

Age < 50 yrs

Ax Diss SN

n = 2 n = 1

Is Z11 a Failed Study?

• Planned accrual 1900, closed at 891

Slow accrual and low event rate

• Pre-defined analysis plan carried out

Non-inferiority of SN by p = .008

• Total LRR, DFS, OS all numerically favor SN group

No suggestion of a power problem

• To reach the 10% LRR threshold suggested by

EBCTCG, LRR in the remaining patients in the SN

group would need to increase 12x.

Survival and Local Control

EBCTCG

Group 5yr ! LR 15yr ! Survival

N-, BCS ± RT 16.1% 5.1%

N+, BCS ±

RT

30.1% 7.1%

N+, M ± RT 17.1% 5.4%

N-, M ± RT 4.0% -3.6%

Z11 ± Ax Diss 0.4% NO CHANCE!

Lancet 2005;366:2087

Giuliano A, JAMA 2011;305:589

Understanding Z11

• Accepting the results of Z11 means recognizing that

some patients will have positive nodes which are not

removed.

• There is NO role for nomograms to predict the likelihood

of additional positive nodes.

Lessons Learned from NSABP B04

Radical Mastectomy

n = 362

Total Mastectomy

n = 365

Median nodes removed 16

40% positive axillary nodes 18.5% delayed

axillary dissection

After mastectomy alone, only " of patients with

involved nodes develop axillary first failure.

Fisher B, NEJM 1985;312:674

Standard Breast Tangents

Treat Some of the Axilla

Axillary Level

Treated to

95% Prescribed Dose

I 79%

II 51%

III 49%

Reznik J, IJROBP 2005;61:163-8

Effective Systemic Therapy

Contributes to Local Control

Fisher B, JCO 1996;14:1982

Romand, NEJM 2005;353:1673

NSABP B13 ER neg NSABP B14 ER pos

No Rx/Placebo 13.4% 14.7%

CTX/Tam 2.6% 4.3%

NSABP B31 HER2 + N9831 HER2+

CTX 2.8% 2.7%

CTX + H 1.7% 1.5%

Fisher B, JNCI 1996;88:1529

Axillary Failure After No Surgery,

Tangent RT + Systemic Rx

Author n

Median f/u

(yrs)

% Ax

Recurrence

Martelli 499 15 3.7*

IBCSG 473 6.6 3.0**

Veronesi 435 5.3 1.5

* T1 only

** RT – 33%

Martelli G, Ann Surg Oncol 2011;18:125

Rudenstam CM, JCO 2006;24:337

Veronesi U, Ann Oncol 2005;16:383

SN only positive node in 70% of cases.

0.9% regional recurrence at 6.3 years completely

consistent with other published studies.

ACOSOG Z11

Why NOT do Axillary Dissection?

Morbidity of Axillary Surgery

n = 821

SN% ALND % p-value

Wound Infection 3 8 .0016

Axillary Paresthesia, 12 mo 9 39 <.0001

Lymphedema, 12 mo

Patient Perceived 6 19 <.0001

Measured 6 11 .0786

Lucci A, JCO 2007;25:3657

Clinical Implications

In clinically node-negative patients undergoing BCT

with macrometastases in the SN:

- Systemic Rx decision made

- ALND not necessary for local control

- ALND does not contribute to survival

Implementing a Policy of

Individualized Axillary Management

T3 or N1

Any T,N + mastectomy

Receiving neoadjuvant rx

• Preop documentation of nodal disease with

US+FNA avoids SN biopsy.

• Frozen section to minimize reoperation

• No IHC for H+E negative nodes.

Implementing a Policy of

Individualized Axillary Management

T1 T2 N0 – Undergoing BCT

• Identification of single abnormal axillary nodes

with US + FNA does NOT change management.

• Cost effectiveness of US to identify extensive

axillary disease in cN0 patients requires study.

• Frozen section of SN no longer routine.

• Patients ! 3 involved SN on final pathology

returned to OR for axillary dissection.