surgical management of the axilla atual da … · tumor size ≤2 cm tumor size >2 cm planned...

PRIVATE AND CONFIDENTIAL 21 May 2010

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Surgical management of the Surgical management of the axillaaxilla

Seema A. Khan MDProfessor of Surgery

Bluhm Family Professor of Cancer Research

Feinberg School of Medicine & the Robert H. Lurie Comprehensive Cancer Center of Northwestern University

4/1/2011

Robert H. Lurie Comprehensive Cancer Center

of Northwestern University Medical School

Brief history of axillary managementBrief history of axillary management

� 100 years ago: consensus that meticulous axillary clearance was essential for survival

◦ Radical mastectomy

� 50 years ago: experiments in clearance of all regional nodes (axillary, supraclavicular and internal mammary)

◦ Extended radical mastectomy

� 25 years ago: axillary clearance is a diagnostic procedure

◦ Modified radical mastectomy

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The completeness of axillary The completeness of axillary surgery affects long term outcomes.surgery affects long term outcomes.

Axillary Dissection vs. none: Randomized Trials

Orr RK. Ann Surg Oncol 1999;6(1):109-16

Survival

All trials reported higher

survival in the AD group


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Courtesy of Paolo Veronesi

Sentinel Node Biopsy Reliably Sentinel Node Biopsy Reliably Stages the Stages the AxillaAxilla

% Nodal Metastases

Axillary Dissection Sentinel Node Biopsy

ALMANAC 23.8% 24.8%

N=1031

Veronesi 32.3% 35.5%

N=516

Mansel RE, JNCI 2006;98:599

Veronesi U, NEJM 2003;349:546


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• Simple, safe and reliable• Reproducible • High predictive value• Low false negative rate

• Do all patients with a positive SN need axillary dissection?

Sentinel Lymph Sentinel Lymph Node biopsy has become Node biopsy has become the gold standardthe gold standard

Clinically Negative Axillary Nodes

GROUP 1SN +AD

SN Neg(SN only)

GROUP 2SN

Stratification• Age• Clinical Tumor Size• Type of Surgery

B-32

SN pos+ AD

SN PosSN Neg(SN+AD)

Intraop cytology & postop HE

FUFU

1,975 patients2,011

patients

Randomization


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BB--32 Analysis Plan32 Analysis Plan

� 3,989 - SN neg (71% of 5611)

� 99.9% - follow-up information

� 95 months - average time on study

� Primary endpoints overall survival, disease-free survival, Regional Control

� Study powered to detect 2% difference in overall survival.

B-32 OS

* 300 deaths triggered the definitive analysis

* 309 reported as of 12/31/2009

NSABP Protocol B-32

Years After Entry

% S

urvi

ving

0 2 4 6 8

020

4060

8010

0

Trt N DeathsSNR+AD 1975 140SNR 2011 169 HR=1.20 p=0.117

Overall Survival for Sentinel Node Negative Patients

Data as of December 31, 2009


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B-32 OS

0 2 4 6 8

0.1

0.2

0.5

1.0

2.0

5.0

10.0

Time after Randomization (Year)

HR

Protocol B-32: Sentinel Negative PatientsSmoothed Hazard Ratio Plots for Mortality

Data as of December 31, 2009

B-32 SN Negative Patients: Hazard Ratios of overall survivalAccording to Stratification Variables

Hazard Ratio

0.2 0.6 1.0 1.4 1.8 2.2 2.6

All patients with follow-up HR= 1.2

Patients < 50 at entry

Patients 50 + at entry

Tumor size ≤ 2 cm

Tumor size >2 cm

Planned Lumpectomy

Planned Mastectomy

SNR+AD betterSNR better


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B-32 SN Negative Patients: HR for Disease-free survival

According to Stratification Variables

Hazard Ratio

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

All patients with follow-up HR= 1.05

Patients < 50 at entry

Patients 50 + at entry

Tumor size ≤ 2 cm

Tumor size >2 cm

Planned Lumpectomy

Planned Mastectomy


B-32 Hazard Ratios Between GroupsAccording to Site of Treatment Failure

Hazard Ratio

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

All events HR= 1.05

Local Regional Recurrences

Distant Recurrences

Opposite Breast Cancers

2nd cancers

Dead, NED



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Group 1 Group 2

Local 54 (2.7%) 49 (2.4%)

Axillary 2 (0.1%) 8 (0.3%)

Extra-axillary 5 (0.25% 6 (0.3%)

Local and Regional Recurrencesas First Events

Group 1SN + AD

Group 2SN

Shoulder abduction deficit 19% 13%

Arm volume difference >5% 28% 17%

Arm numbness 31% 8%

Arm tingling 13% 7%

All differences p<0.001

Residual Morbidity at End of Follow-up

Ashikaga et al JSO in press

• Lower in SN group• Not nonexistent


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Kuehn T et.al, Br Cancer Res Treat 2000;64:275-86.

Locoregional Morbidity:Locoregional Morbidity:The Axilla in ContextThe Axilla in Context

% of pts

n = 396

DOES A DOES A POSTIVEPOSTIVE

SENTINEL NODE BIOPSY SENTINEL NODE BIOPSY

REQUIRE AXILLARY REQUIRE AXILLARY

DISSECTION?DISSECTION?

A pathologically negative sentinel node biopsy is as informative and less morbid than axillary dissection

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Until 2010: Approach Until 2010: Approach to the Positive to the Positive SNSN

� Determine risk of additional positive nodes

� If risk sufficiently high proceed with axillary dissection

-Metastases on frozen section- proceed with immediate dissection

-Metastases on final path- consider nomograms and if risk of additional nodes high proceed with axillary dissection

Can ALND Be Avoided in SN Can ALND Be Avoided in SN Negative or SN Positive Patients?Negative or SN Positive Patients?

# patients # axillary LR (%)

Median FU( months)

Median timeto axillaryrecurrence

SN negative14 studies2004-2006

3802 24 (0.3%) 47 months 19 months

SN positive6 studies2003-2007

583 3 (0.5%) 31 months 22 months

Rutgers E, JCO 2008;26:698


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ACOSOG Z0011 Study Design

Giuliano AE et al JAMA 2011

ACOSOG ZACOSOG Z--00110011

4/1/2011 JSV/

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

� Matted nodes

� 3 or more involved SN



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Study Population SchemaStudy Population Schema5/99 5/99 –– 12/0412/04

Giuliano A: Annals of Surgery 252:3; 426 September 2010

Intent-to-treat analysis

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ACOSOG Z0011: Patient CharacteristicsACOSOG Z0011: Patient Characteristics

Age (median range)

Clinical Stage T1T2

ER(+)(-)

LVI YesNo

56 (24-92)

67.9%32.1%

83.0%17.0%

67.7%32.3%

40.6%59.4%

ALND (420 pts)

54 (25-90)

29.4%

17.0%

64.8%

70.6%

83.0%

69.9.%

35.2%

SLND(436 pts)

30.1%

PR(+)(-)



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ACOSOG Z0011: Median Number of ACOSOG Z0011: Median Number of Lymph Nodes RemovedLymph Nodes Removed


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Size of Sentinel Node MetastasesSize of Sentinel Node Metastases


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Locoregional recurrence in Locoregional recurrence in ACOSOG Z0011ACOSOG Z0011� Locoregional recurrences: 16 (4.1%) in ALND group compared with 12 (2.8%) in SLND alone.

� Local recurrence 14 (3.6%) ALND group compared with 8 (1.9%) in SLND alone.

� Regional recurrence: 2 (0.5%) patients in ALND compared with 4 (0.9%) patients in SLND alone group.

Giuliano AE et al Annal of Surgery 2010

Figure 2. Survival of the ALND Group Compared With SLND-Alone Group

Giuliano, A. E. et al. JAMA 2011;305:569-575

Copyright restrictions may apply.

Axillary recurrences 0.9% in SN group and 0.5% in ALND group


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Figure 3. Hazard Ratios Comparing Overall Survival Between the ALND and SLND-Alone Groups



ACOSOG Z0011: Adjusted Hazard Ratios for Overall ACOSOG Z0011: Adjusted Hazard Ratios for Overall Survival Comparing SLNDSurvival Comparing SLND--Alone Alone vsvs ALND Groups.ALND Groups.



Model variables Number patients

Numberevents

Adjusted HR (90% CI)

SN vs. AND + age + systemic therapy

839 92 0.87 (.62, 1.23)

Add tumor size* 818 92 0.89 (0.62, 1.25)

Add ER status* 778 87 0.92 (0.64, 1.30)

Add Grade* (1 vs. 2 vs. 3) 839 92 0.86 (0.61, 1.21)

Add histology* (duct vs. lobular)

839 92 0.88 (0.63, 1.25)

All additional models show variables added one at a time to model in row 1

DFS analyses show identical, non-significant trend.


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Can we believe the ZCan we believe the Z--0011 results0011 results

� No

◦ Sample size as less than half that planned

◦ Study was closed for non-accrual

◦ Results are therefore not valid.

� Yes

◦ There are 400+ patients per group

◦ The randomization insures balance/lack of bias

◦ The event rates are so low that even if accrual had reached the goal, the results would be the same.

Time to axillary recurrence: metaTime to axillary recurrence: meta--analysis of 48 SN studiesanalysis of 48 SN studies

Van der Ploeg et. al.


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.

JCO 2006;24:337-344

©2006 by American Society of Clinical Oncology

Rudenstam C-M et. al.

IBCSG trial 10-93:

Randomization of 473 women >age 60, cN0 Randomization of 473 women >age 60, cN0

Neoadjuvant systemic therapyNeoadjuvant systemic therapyKey Key (and controversial) surgical (and controversial) surgical questions.questions.

� Timing of sentinel node biopsy

� Is axillary dissection always necessary for the positive sentinel node?

�What is the role of pre-therapy axillary ultrasound?


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Benefits of PreBenefits of Pre--treatment sentinel node treatment sentinel node biopsybiopsy

� Accurate assessment of initial nodal stage.

� May affect plans for post-mastectomy or nodal radiotherapy.

� Accuracy of pre-treatment sentinel node evaluation is better established.

Benefits of postBenefits of post--therapy sentinel node therapy sentinel node biopsy.biopsy.

� Eliminates the need for two surgical procedures� Assess the ability of the preoperative therapy to

achieve a pathologic complete response.� Fewer patients require an axillary lymph node

dissection because of down-staging effect of preoperative chemotherapy.

� Does not delay administration of preoperative chemotherapy


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Sentinel node timing: metaSentinel node timing: meta--analyses analyses of resultsof results

sentinel node biopsy timing

Mapping success

False negative rate

Number of patients

Study period

De novo (Giuliano)

96.4% 7% 8,059 1970-2003*

Post systemic therapy (Kelly

89.6% 8.4% 1,799 2000-2007

Reports since 2003 include and additional ~10,000 women with mapping success >96% & false negative rate 5-10%

SN post neoadjuvant therapySN post neoadjuvant therapy

MetaMeta--analysis: 1794 patients, 24 trials, 2000analysis: 1794 patients, 24 trials, 2000--20072007

Kelly AM et. al. Acedemic Radiol 2009

Summary success rate 89.6%, (95% CI 86-92%)


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False negative rate sentinel node False negative rate sentinel node post neopost neo--aduvant therapyaduvant therapy

Kelly AM et. al. Acedemic Radiol 2009

Summary false negative rate 8.4%, (95% CI 6.4-10.9)

4/1/2011 JSV/Kirkpatrick KK et. al. SABCS 2010

Axillary ultrasound for prediction of Axillary ultrasound for prediction of nodal diseasenodal disease


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Axillary US & MSKCC Axillary US & MSKCC nomogramnomogram

4/1/2011

JSV/kirkpatricj

Kirkpatrick KK et. al. SABCS 2010

Assessment of the axilla in the setting Assessment of the axilla in the setting of neoadjuvant systemic therapy of neoadjuvant systemic therapy requires multidisciplinary discussionrequires multidisciplinary discussion

� Consider pre-op SN if

◦ Will establish indication for chemotherapy

◦ Will alter plans for radiotherapy

� Pre-therapy US + needle bx may establish nodal disease

� Post-therapy SN appropriate for

◦ Patients clearly needing chemotherapy for systemic risk management

◦ With radiotherapy consultation

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SummarySummary� Sentinel node biopsy is the standard of care for the node negative patient.

� The value of axillary clearance in patients with low-volume axillary disease is decreasing.

◦ ACOSOG Z0011 results show no benefit for women with 1-2 positive sentinel nodes.

� Axillary clearance is standard of care for SN +

◦ women undergoing mastectomy,

◦ those with clinically positive axillae,

◦ gross extranodal extension

◦ Following neoadjuvant systemic therapy

4/1/2011 JSV/

surgical management of the axilla atual da … · tumor size ≤2 cm tumor size >2 cm planned...

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