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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.