Tangents ONLY for Sentinel Lymph Node Positive Breast ...

Tangents ONLY for Sentinel Lymph Node Positive Breast Cancer

(Skip the RNI)

Henry Kuerer, MD,PhD,FACSDepartment of Surgical Oncology

University of Texas MD Anderson Cancer Center

Disclosures• Employment/Compensation

– MD Anderson Cancer Center; Editor, McGraw‐Hill

• Research funding support– Genomic Health, Inc.

• Scientific advisory board– Lightpoint Medical, Inc.

Outline• Focus breast conserving surgery, SLN

positive disease in one or two nodes, whole-breast radiotherapy

• Clinical trials in relation to MA.20– IBCSG 23-01– ACOSOG Z11– AMAROS

NCCN Guidelines Lumpectomy1-3 positive nodes

• 42% SLNB vs 29% ALND (p<0.03)

• Micrometastases– 16% SLNB vs

3% ALND (p<0.0005)

• SLN era of detection more like historical node-negative disease

SLN Era: significantly higher axillary metastatic node detection

Giuliano et al Ann Surg, 1995

Decreasing nodal burden: stage migration• MD Anderson Cancer Center• Number positive nodes, axillary dissection• 1978 – 1997

– 1 + 45%– 2 + 32%– 3 + 23%

• 2000 – 2007– 1 + 55%– 2 + 30%– 3 + 15%

McBride et al, Int J Radiation Oncol Biol Phys, 2014

Risk of additional positive nodes after positive SLN whole-breast radiation trials

• Randomized trials that included ALND after (+) SLN: Additional (+) nodes 13 to 27% (before administration of systemic therapy)

• Axillary nodal recurrence in SLN surgery alone arms <1%

• IBCSG 23-01, ACOSOG Z11

Tangential Fields: Design Determines Axillary Nodal Coverage

High TangentsStandard Tangents

Incidentally includes level I part II Deliberately includes level I-II higher and deeper borders

What is Regional Node Irradiation?• Many definitions, may

be unspecified• Can include:

– Supraclavicular– Internal mammary– Level III– Axillary fields (level I/II)

MA.20

Why consider RNI for Early Breast Cancer?

• Node negative and 1 to 3 positive lymph nodes

• L III, SC, IM may serve as occult reservoir for disease, never clinically apparent, but source for distant disease– Unpublished; NCIC MA.20 and EORTC 22922

MA.20:2000-2007

A Phase III Study of Regional Radiation Therapy

in Early Breast Cancer Whelan et al ASCO 2011

®Stratification Axillary nodes removed (<10, >10) Positive axillary nodes (0, 1-3, >3) Chemotherapy (anthracycline, other, none) Endocrine therapy (yes, no)

MA.20 StudyNode positive or high risk

node negativeafter BCS

Whelan et al ASCO 2011

WBI

WBI + RNI

n=916

n=916

MA.20 PopulationEligibility Criteria: Treated with BCS and sentinel node biopsy

(39%) or axillary node dissectionNOTE: all node +ve patients treated with a level 1 and 2 axillary dissection; 85% of patients in study 1-3 node positive Treated with adjuvant chemotherapy and/or

endocrine therapy


Isolated Locoregional DFS

* 67% of regional recurrences were in the axilla

Any First Local or Regional Recurrence WBI WBI + RNI

N of Patients 916 916Events 48 29

Local only 25 25Regional only* 21 4Local + Regional 2 0

5-Yr LR DFS 94.5% 96.8%2.3%


HR=0.64 (95% CI 0.47 to 0.85)P=0.002 (Stratified)

−WBI −WBI + RNI

Distant DFSPe

rcenta

ge

0

20

40

60

80

100

Years

0 1 2 3 4 5 6 7 8 9 10

92.4%87%


HR=0.76 (95% CI 0.56 to 1.03)P=0.07 (Stratified)

−WBI −WBI + RNI

Overall Survival

Perce

ntage

0

20

40

60

80

100

Years0 1 2 3 4 5 6 7 8 9 10

92.3%90.7%


Why not consider RNI for Early Breast Cancer?

• Long term survival > 80%• Potential long term toxicity becomes real

concern– Heart, lung, esophagus– Lymphedema– Arm mobility– Cosmesis, malignancy

EORTC phase III trial 22922/10925 SC-IMEarly reported toxicity up to 3 years

• Cardiac disease–1.4% IM-MS vs. 1.6% none; p=0.64

• Lung toxicity–4.3% IM-MS vs. 1.3% none; p<0.0001–(fibrosis, dyspnea, pneumonitis)

Matzinger et al., Acta Oncologica, 2010

WBIn=927

WBI + RNIn=893

PValueGrade 2 3 4/5 Any 2 3 4/5 Any

AcuteRadiationDermatitis 349 23 - 40% 397 45 - 50% <0.001

Pneumonitis 2 - - 0.2% 12 - - 1.3% 0.01

DelayedLymphedema 34 3 1 4% 61 4 - 7% 0.004

*NCI Common Toxicity Criteria v.2 1998

MA.20 Adverse Events*Grade ≥ 2


WBI WBI + RNI P Value

Baseline 187 / 910 (21%) 197 / 876 (22%) 0.33

At 3 years 177 / 679 (26%) 195 / 670 (29%) 0.22

At 5 years 111 / 381 (29%) 142 / 396 (36%) 0.047

* Number (%) of Patients with fair or poor global assessment of cosmetic outcome using the EORTC cosmetic rating system

MA.20 Adverse Cosmetic Outcome*


International Breast Cancer Study Group (IBCSG) Trial 23-01: N1mi, N=931

Galimberti, et al. Lancet Oncol 2013

• Phase III randomized trial of ALND vs SLND only• cT1-2 N0 patients with micromets (≤ 2mm) in ≥ 1 SLN• In ALND group, 59 (13%) had additional positive nodes• 9% of patients in each arm underwent mastectomy

Median f/u 5 years ALNDN=464

SLND onlyN=467

Local recurrence 10 (2%) 8 (2%)

Regional recurrence 1 (<1%) 5 (1%)

Distant recurrence 34 (7%) 25 (5%)

Radiation Fields IBCSG 2301• Unknown, ‘extent of incidental axillary

radiation is not ascertainable’• 22% no WBXRT (none or ELIOT PBI)• Authors suggest that low rate of nodal

recurrence could be immunosurveilance

IBCSG 23-01 Survival Endpoint

Galimberti, et al. Lancet Oncol 2013

ALNDN=464

SLND onlyN=467

HR(95% CI) P value

5 yr DFS 84% 88% 0.78 (0.55 – 1.11) 0.16

5 yr OS 98% 98% 0.89 (0.52-1.54) 0.73

ACOSOG Z0011: All patients node positive detected by SLN biopsy

Primary Objective: To assess whether OS after SLND alone was not inferior to that for patients who

underwent completion ALND for a positive SLN

Patient and tumor characteristics

Giuliano, et al. Ann Surg, 2010

ALNDN=420

SLNDN=436

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

Clinical T1 68% 71%

Ductal histology 83% 84%

ER+ 83% 83%

GradeIIIIII

22%49%29%

26%47%28%

LVI 41% 35%

Adjuvant systemic therapy

ALNDN=420

SLNDN=436

Chemotherapy 57.9% 58.0%

Hormonal therapy 46.4% 46.6%

Either/Both 96.0% 97.0%


Size of SLN metastasis

0

10

20

30

40

50

60

70

Micrometastasis(<2.0mm)

Macrometastasis

Perc

ent o

f Pat

ient

s

ALND

SLN

37.5%44.8%

62.5%

55.2%

P=0.05

Giuliano A, et al. JAMA, 2011

Additional positive LNs

106 (27.3%) of patients treated with ALND had

additional positive nodes removed beyond the SLN


Z0011:Local-regional recurrence

ALNDN=420

SLNDN=436

Local 15 (3.6%) 8 (1.8%)

Regional 2 (0.5%) 4 (0.9%)

Total 17 (4.1%) 12 (2.8%)

Node-positive Disease


Z0011:Overall survival

Giuliano, et al. JAMA, 2011 Median follow-up: 6.3 yr

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

live

ALNDNo ALND

P-value = 0.25

93%92%

Z0011:Disease-free survival

Giuliano, et al. JAMA, 2011 Median follow-up: 6.3 yr

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% R

ecur

renc

e-Fr

ee and

Aliv

e

ALNDNo ALND

P-value = 0.14

84%82%

Z0011:Conclusions

• For patients with cT1-2 N0 breast cancer and 1-2+ SLN undergoing BCS with whole breast RT:– No improvement in regional control with ALND– No impact on survival

• Does not apply to:– Clinically node positive– Patients receiving neoadjuvant chemotherapy– Patients undergoing mastectomy

Z0011:Conclusions• For patients with cT1-2 N0 breast cancer and 1-2+ SLN

undergoing BCS with whole breast RT:– No improvement in regional control with ALND– No impact on survival

• Does not apply to:– Clinically node positive– Patients receiving neoadjuvant chemotherapy– Patients undergoing mastectomy– Patients receiving partial breast irradiation

Radiation Fields and RNI ACOSOG Z11(Alliance) Trial

• Case report forms: 605 patients• 89% WB; 11% NO RADIOTHERAPY• 15% supraclavicular field

• 228 detailed RT records• 81.1% tangents only, 18.9% ≥ 3 fields, more common

with greater nodal involvement (p<0.001)• High-tangents used 50% of patients each arm

Jagsi et al, J Clin Onc, 2014

Radiation Fields and RNI ACOSOG Z11(Alliance) Trial

• No significant difference in RNI in SLN only versus ALND groups

• The primary finding – that routine ALND is not necessary after +SLNB in one or two nodes–stands

Jagsi et al, J Clin Onc, 2014

Can axillary radiotherapy substitute for axillary dissection?

Is it actually necessary after a positive SLN?

AMAROS:EORTC 10981-22023• After mapping axilla: radiation or surgery?• Hypothesis: AxRT provides comparable local control and survival as ALND with

fewer side effects• cT1b-2 N0• BCT or mastectomy

• Pos SLN randomized to ALND or AxRT

cT1-2N0 R SNB

ALND

AxRT

AxSN+

AxSN-Rutgers E, ASCO 2013

N=1,425

• Extent:level I + II + III + medial SC

• Dose & schedule:25 x 2 Gy or equivalent

• Quality control:dummy run

Hurkmans et al, Radiother Oncol 2003; Rutgers, ASCO 2013

AMAROS Radiation Fields

AMAROS Nodal Recurrence• In ALND group, 244 (32.8%) patients had additional

positive nodes• Median follow-up = 6.1 years

ALNDN=744

AxRTN=681

Axillary recurrence 0.43% 1.19%

Axillary recurrence in SLN negative patients = 0.72%

Rutgers E, ASCO 2013

AMAROS• No difference in DFS or OS

HR:1.17; 95CI: 0.85-1.62HR:1.18; 95CI: 0.93-1.15


AMAROS Lymphedema• Decreased lymphedema with AxRT


0

5

10

15

20

25

30

35

40

1 3 5

ALND

AxRT

28.0%

40.0%

29.8%

21.7%

16.7%13.6%

Years after randomization

P < 0.0001 P < 0.0001P < 0.0001

Perc

enta

ge

*lymphedema observed or treated

Z0011/AMAROS

• Lymphedema rates• ALND 28%• AxRT 14%• SLND 5%

• Based on Z0011, 82% of patients enrolled on AMAROS could have avoided both ALND and AxRT

AMAROS/Z11 Conclusions

• Ax radiotherapy and ALND provide effective local regional control in SLN + patients

• Additional benefit of Level III and SC radiotherapy fields not clear

• Long term lymphedema rate significant concern

Individualization: Patient Selection• Nomograms to predict risk of >4 positive

nodes in non-dissected axilla?– “If greater than 30% strongly consider L III/SC”

• Will performing axillary dissection change field selection? 1/14; 2/20; 3+– What nodal fields will you treat?

Katz et al J Clin Oncol, 2008Haffty, Hunt, Harris, Buchholz, J Clin Onc, 2011

De‐escalating therapy: NSABP B‐51/RTOG1304

Primary aim: Evaluate whether the addition of PMRT and regional nodal irradiation will improve invasive DFS rates

Clinical T1‐T3, N1 Breast Cancer

Neoadjuvant Chemotherapy

Pathologically negative lymph nodes (either by SLND or ALND)

No PMRT or regional nodal XRT

Regional nodal XRT

Stratification Factors:• Surgery type (lumpectomy, mastectomy• Hormone receptor status• HER2 status• Adjuvant chemotherapy (yes/no)• pCR in breast (yes/no)

Randomization

N=1,636

Can genomic profiling lead to better selection for minimizing

extent of radiotherapy?

Summary• Local regional control and survival excellent among

patients with SLN + disease receiving WBXRT and systemic therapy

• Use of RNI is associated with significant additional toxicity

• Results for RNI in earlier stage breast cancer (1-3+ and node negative)– Potentially profound and practice changing

Conclusion: Tailoring Local Therapy

• Breast Cancer is a heterogeneous disease• Many groups do extremely well focus on omission, cost, convenience focus on toxicity avoidance

• Selected groups need improvements focus on new therapeutic approaches

AcknowledgementsSurgical Oncology

Kelly K. Hunt, MDGildy V. Babiera, MDIsabelle Bedrosian, MDShon Black, MDAbigail S. Caudle, MDSarah M. DeSnyder, MDBarry W. Feig, MDRosa F. Hwang, MDAnthony Lucci, MDFunda Meric-Bernstam, MDMediget Teshome, MD

Breast Medical OncologyBanu Arun, MDMariana Chazez, MD Gabriel N. Hortobagyi, MD Jennifer K. Litton, MDVicente Valero, MD

PathologyAysegul A. Sahin, MDMichael Gilcrease, MDSavitri Krishnamurthy, MD

Radiation OncologyThomas A. Buchholz, MDWelela Tereffe, MDEric Strom, MDSimona Shaitelman, MDBen Smith, MDMichael Stauder, MDGeorge Perkins, MDWendy Woodward, MD, PhD

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