The Management of Breast Cancer · PDF file5 Models of Breast Cancer Halstedian 1900 –1970’s A local-regional disease Justification for more radical surgery / radiation Fisher

2015 ASTRO Spring Refresher

The Management of Breast Cancer

Gary M. Freedman, M.D.

Associate Professor

2

Disclosure

I have no conflicts of interest to disclose.

3

Learning Objectives

Apply knowledge of randomized prospective trials to guide the

selection process for radiation in early stage breast cancer.

Be able to predict based upon current studies whether a

patient is low, intermediate or high risk for local or regional

recurrence without radiation.

Determine through enhanced knowledge of the evidence

based indications optimal patient selection for radiation

treatment to regional lymphatics, hypofractionation or

accelerated partial breast irradiation approaches.

Local Therapy and Survival in Breast Cancer

Introduction

5

Models of Breast Cancer

Halstedian 1900 – 1970’s

A local-regional disease

Justification for more radical

surgery / radiation

Fisher 1970 – 1990’s

A systemic disease

Justification for less radical

surgery / radiation but more

systemic therapy

http://upload.wikimedia.org/wikipedia/commons/a/a5/William_Stewart_Halsted_Yale_College_class_of_1874.jpg

http://upload.wikimedia.org/wikipedia/commons/a/a5/William_Stewart_Halsted_Yale_College_class_of_1874.jpg

http://upload.wikimedia.org/wikipedia/commons/9/98/Nci-vol-8226-300_bernard_fisher.jpg

http://upload.wikimedia.org/wikipedia/commons/9/98/Nci-vol-8226-300_bernard_fisher.jpg

6

NSABP B-04

“3 Levels” of Axillary Treatment (including regional node RT)

No differences in survival

Fisher et al NEJM 347: 567-75; 2002.

7

NSABP B-06

Fisher et al N Engl J Med 2002; 347:1233-41.

“3 Levels” of Breast Treatment

RT recommended for breast conservation not survival

8

CS + RT: Equal Survival as Mastectomy

NCI Consensus Conference June 1990

Breast conservation treatment is an appropriate method of

primary therapy for the majority of women with stage I and II

breast cancer and is preferable because it provides survival

rates equivalent to those of total mastectomy and axillary

dissection while preserving the breast.

Final nail in the Halstedian coffin

There was an unstated assumption that mastectomy

local control is probably better.

JAMA 265: 391-5; 1991

9

WHY GIVE PMRT? JUST LOCAL CONTROL FOR LOCALLY

ADVANCED OR INFLAMMATORY CASES?

WHY CARE ABOUT LUMPECTOMY MARGINS?

In the year 1990 …

If local control does not affect survival …

Does the patient selection for breast conservation, or the quality

of the surgery or radiation matter?

10

Spectrum Model 1990’s - Present

Local-regional treatment will

have an impact on survival in

some patients

Justification for careful patient

selection and techniques for

both breast conservation and

postmastectomy radiation.

11

The Spectrum Model

PrimaryTreatment

LocalFailure

LocalandDistantFailure

DistantFailure

NoFailure

Alive DistantFailure

Dead(Early)

Dead(Late)

TIME

RT RT

Prevent

This!

Not every local recurrence prevented improves survival – but some do.

12

PMRT – 1st failures are not the whole story

MRM ± radiation

Node positive patients after 15 years

No chemotherapy/endocrine therapy

No XRT XRT Difference

First Failure

Local Failure 37% 10% - 27%

Distant Metastases 34% 43% + 9%

Total Failure

Local Failure 56% 19%

Distant Metastases 72% 54% - 18%

Death 70% 61% - 9%

Arriagada et al. JCO 13:2869 1995

13

Early Breast Cancer Trialists’ Collaborative Group

Lancet 2005; 366: 2087–2106

Message: Survival benefit is a result of the local-regional control benefit.

1 / 4 Ratio: One death from breast cancer avoided for every four LR recurrences avoided.

14

Local Control Benefit Predicts the Late Survival Benefit

EBCTCG Lancet 383: 2127-2135; 2014

No LC

No Surv

Big LC

Big Surv

T1-T2 Invasive Breast Cancer

16

BCT absolute contraindications

• Multicentric disease (tumors in more than one quadrant)

• Multifocal permitted if resected by single incision

• Diffuse or suspicious microcalcifications

• Persistently positive margins despite multiple re-excisions

• Unless an anatomic boundary

• Previous breast or chest RT

• Pregnancy

• Collagen vascular disease

• Scleroderma

• Active lupus?

• Not RA

17

BCT relative contraindications

• Ratio of tumor size to breast unacceptable for good cosmetic

outcome

• Neoadjuvant chemo may be attempted to convert the patient to a

candidate for BCT

• T3

– Neoadjuvant chemo may be attempted to convert the patient to a

candidate for BCT

• Subareolar location

• Patients may choose to sacrifice nipple

• BRCA 1/2

• Survival outcomes with mastectomy equal

• Patients may accept high rate of new primaries

18

MRI: A Coin Flip?

Affect of MRI on clinical management

22% affected management

• Examples - MRI-prompted mastectomy or additional biopsy

Almost equal chance of help or harm

• Can you prove favorable effects were all really improving outcome?

• How do you know an add’l focus would be source of LR?

Tillman et al J Clin Oncol

20: 3413-22; 2002.

19

Meta-Analysis of MRI

9 studies

3,112 patients

Increase in mastectomy

No reduction in positive

margins, re-excisions

Houssami et al Ann Surg

2013;257:249-55.

20

Meta-Analysis of MRI

4 studies

3,169 patients

8-yr LR-free survival

97% vs. 95%

HR MRI vs. No MRI

0.88 (0.52-1.51)

p=0.65

Houssami et al J Clin Oncol

2014;32:392-401.

21

BCS + RT Invasive Breast Cancer

Factors associated with local recurrence

Higher Lower

• Positive margin Boost

• Young age Systemic Therapy

• Subtype

22

Margins Meta-Analysis and Consensus

Tumor on ink = positive margin

Overall median rate of IBTR 5.3%.

Makes non-significant differences in 1, 2 and 5 mm not

clinically significant either.

Moran et al Int J Radiat Oncol Biol Phys

88: 553-64; 2014.

23

Re-excision of Margins

Invasive Breast Cancer

American College of Radiology A re-excision should be performed for an involved margin.

Wider margins may be more important in select patients (young, estrogen receptor

negative, or extensive intraductal component).

American Society of Breast Surgeons Margin ≥ 1 mm usually adequate

Consider re-excision for focally positive or < 1mm margins on a case-by-case basis.

Re-excision usually needed for a positive margin.

American Society of Clinical Oncology Endorses adoption of the SSO/ASTRO Guideline – but flexibility in the application of

the guideline is needed in some areas.

Heightened emphasis needed on the importance of postlumpectomy mammography for

cases involving microcalcifications.

National Comprehensive Cancer Network A positive margin should generally undergo further surgery.

Exceptions may be made for selected cases of focally positive margin and absence of

extensive intraductal component.

Society of Surgical Oncology / American

Society for Radiation Oncology

A positive margin should be defined as no tumor on ink.

Negative margins are optimal for local control in most situations.

Wider margins than no tumor on ink are not routine indications for further surgery.

24

Local Recurrence By Age - Then

Bartelink et al J Clin Oncol

25: 3259-3265; 2007.

25

Young Age – Now

Arvold et al J Clin Oncol

29:3885-3891; 2011.

Today the age effect is much diminished

Selection Factors: BRCA, Imaging

Treatment Factos: Margins, Systemic Therapy, Boost

26

BCS + RT by Subtype

Hattangadi-Gluth et al Int J Radiat Oncol

Biol Phys 82: 1185-91; 2012.

27

Young Age – Biology

Arvold et al J Clin Oncol

29:3885-3891; 2011.

Predictor AHR 95% CI P

Age, years 0.97 0.94 to 0.99 .009

BC subtype

Luminal A 1 (reference) — —

Luminal B 2.14 0.95 to 4.85 .067

Luminal HER2 0.48 0.06 to 3.73 .49

HER2 5.15 1.76 to 15.05 .003

Triple negative 3.94 1.72 to 9.01 .001

No. of positive nodes 1.07 1.00 to 1.16 .059

Tumor size, cm 1.32 0.96 to 1.80 .08

WB dose, Gy 0.91 0.86 to 0.98 .007

Adjusting for biology now the age effect is much diminished

Margins – not significant?

28

Young Age – Biology

Demerci et al Int J Radiat Oncol Biol Phys

83: 814-820; 2012.

Adjusting for biology now the age effect is much diminished

29

LOCAL CONTROL TODAY

Survival is equal …

But is it still the case that local control is better with

Mastectomy versus BCS + RT?

30

BCS + RT: Node Positive

Wapnir et al J Clin Oncol 2006; 24:2028-37.

NSABP

BCS + Whole Breast Radiation. No Boost.

31

BCS + Hypofractionated Radiation

UK START B

Haviland et al Lancet Oncol 2014; 14:1086-94.

32

BCS + RT: Margins Meta-Analysis

Overall median rate of IBTR 5.3%.

Includes positive close margins, low systemic therapy

utilization in older studies.

Houssami et al Ann Surg

Oncol 21:717–730; 2014.

33

BCS + RT vs. Mastectomy

T1-2 N0 triple negative

Abdulkarim et al J Clin Oncol

29:2852-2858; 2011.

34

BCS + RT vs. Mastectomy

T1-2 N0 triple negative

Zumsteg et al Ann Surg Oncol

20:3469–3476; 2013

Are there any subgroups of patients

with T1 for whom we can safely omit

adjuvant radiation?

36

Local Control Benefit Predicts the Late Survival Benefit

EBCTCG Lancet 378:771-84; 2011.

37

EBCTCG – BCS +/- RT

No subgroup without

a benefit from RT

38

CALGB

10 years local recurrence 10% vs. 2%

21 of 334 deaths from breast cancer (6%).

Cause-specific survival 98-99%.

Hughes et al J Clin Oncol 31:2382-7; 2013.

39

PRIME II

Age 65 or older

Hormone-positive

Low-grade

Node negative

5-year IBTR 4.1% vs. 1.3%

San Antonio 2013

Older (>70) or reduced life expectancy

T1

N0 (doesn’t have to be pN0 always)

ER or PR +

Margin –

Willing / able to take 5 years endocrine therapy

Willing to accept modest higher local recurrence


with T1 for whom we can safely omit

adjuvant radiation?

Shortening Postlumpectomy Radiation

42

WHOLE BREAST

HYPOFRACTIONATION

RESULTS

‘‘Modern” Trials – Pre 2002!

43

Phase III Trials of Whole Breast Hypofractionation

Years Fractionation Boost Local Time

Trial Conducted # Gy/# of fractions (%) Recurrence (%) Point

RMH/GOC 1986-1998 470 50/25 74 12.1 10 years

466 42.9/13 75 9.6

474 39/13 74 14.8

START A 1998-2002 749 50/25 60 6.7 10 Years

750 41.6/13 61 5.6

737 39/13 61 8.1

START B 1999-2001 1105 50/25 41 5.2 10 Years

1110 40/15 44 3.8

OCOG 1993-1996 612 50/25 0 6.7 10 Years

622 42.5/16 0 6.2

RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre

START: Standardization of Breast Radiotherapy

OCOG: Ontario Clinical Oncology Group

44

OCOG Randomized Trial

42.5 Gy 50 Gy

Cosmesis gd/exc 70% 71%

Whelan et al

N Engl J Med 362:513-20; 2010

Whelan et al N Engl J Med 362:513-20; 2010.

45

UK START A/B Cosmetic Outcomes

Haviland et al Lancet Oncol2014; 14:1086-94.

46

ASTRO Consensus Conference

Hypofractionated WBI was

suitable outside of a clinical trial

in the following patients:

• pT1-2 tumor size

• node negative

• age greater than 50 years old

• patients who do not receive

chemotherapy.

42.5 in 16 fractions

recommended for WBI

The task force did not reach

consensus on hypofractionated

WBI when a tumor bed boost

was thought to be indicated.

My Guidelines

• DCIS or invasive

• Node positive or node negative

• Any age

• Any chemo

• Sequential boost allowed

Avoid hypofractionation for

• Large dose inhomogeneity

• Regional node irradiation

Smith et al Int J Radiat Oncol Biol Phys 2011.

47

2D Planning 80-90’s – Wedged Tangent

Central axis contour.

Goal of 10% or lower

dose inhomogeneity.

Off-axis inhomogeneity

even higher.

Prescription

Point

Chest Wall/Lung

48

2000’s - Simple Forward Planning

Basic

segments

over hot

spots in

beams’ eye

views

CTV/PTV

not needed

Vicini et al Int J Radiat Oncol Biol

Phys 2002; 54:1336-44

49

Modern Volume-Based 3D Planning

PTV and PTVeval Structures

50

Volume Based Forward Planning

3D Conformal Field in Field Forward Planning

51

Volume Based Inverse Planning

IMRT Inverse Planning – Sliding Window

52

Isodose Distribution

Same DVH Goals for

3D or IMRT:

PTVeval 95% > 95%

V105 < 10%

V110 = 0%

53

R ARM 1: Standard fractionation

A Whole Breast 50 Gy / 25 fractions / 2.0 Gy daily

N Optional fractionation of 42.7 Gy in 16 fractions permissible

D Sequential Boost 12 Gy /6 fractions /2.0 Gy daily or

O 14.0 Gy /7 fractions /2 Gy daily

M

I ARM 2: Hypofractionation (15 fractions total)

Z Whole Breast 40 Gy/15 fractions/2.67 Gy daily

E Concurrent boost 48.0 Gy/3.2 Gy daily

RTOG 1005

Stratify

Age < 50 vs. ≥ 50

Chemotherapy Yes/No

ER positive/negative

Histologic Grade 1, 2 vs. 3

5/24/2011 – 6/20/2014

Targeted Accrual 2312

A PHASE III TRIAL OF ACCELERATED WHOLE BREAST

IRRADIATION WITH HYPOFRACTIONATION PLUS

CONCURRENT BOOST

VERSUS

STANDARD WHOLE BREAST IRRADIATION PLUS

SEQUENTIAL BOOST

FOR EARLY-STAGE BREAST CANCER

54

APBI

Accelerated Partial Breast Irradiation

55

Watch for

tissue conformance

skin distance

Arthur and Vicini J Clin Oncol 23:1726-

35; 2005.

RTOG 04-13 / NSABP B-39

Simplest dosimetry.

Treats 1-2 cm around lumpectomy cavity.

Less operator skill dependent.

Intracavitary Balloon Catheter Radiation

56

1,449 cases

Local recurrence

MammoSite Registry

Shah et al Ann Surg Oncol

20:3279–3285; 2013

57

Complications in Catheter APBI

Device removal

Catheter leak

Catheter rupture

Infection

Seroma

Skin toxicity

Fat Necrosis

Fibrosis

Telangiectasia

58

3D Conformal External Beam

38.5 Gy in 10 fractions BID for 5 days.

Noninvasive.

Better dose homogeneity than brachytherapy.

Needs greater margin for set-up and motion.

Vicini et al Int J Radiat Oncol Biol

Phys 63: 1531-7; 2005

59

Results of 3D Conformal APBI

Vera et al Practical Rad Onc 4:147-52; 2014.

60

RAPID: Randomized Trial of Accelerated Partial Breast Irradiation

Age 40 or older

DCIS, T1 or T2 < 3 cm

Negative Margin

Non-lobular

Whole Breast:

• 42.5 Gy / 16 fx

• 50 Gy / 25 fx

• Boost allowed

Versus

APBI:

• 38.5 Gy / 10 fx BID

• 3D CRT only

Olivotto et al J Clin Oncol

31:4038-45; 2013.

61

Wazer et al Int J Radiat Oncol Biol Phys

64: 489-495; 2006.

DHI = Dose Homogeneity Index

Multicatheter Interstitial Brachytherapy

Importance of

Technique

Operator Dependent

• Volume as low as

possible

• Minimize hot spots

• Dose uniformity must

be high

• Watch skin and chest

wall dose

62

National Institute of Oncology Budapest, Hungary

Randomized Trial

• Arm I: External Beam Whole Breast RT 2 Gy x 25 fractions

• Arm II: APBI

– Interstitial 5.2 Gy x 7 fx

– Electrons 2 Gy x 25 fx

Selection Criteria

• T1

• N0 – N1mic

• Grade 1-2

• Nonlobular

• No extensive in-situ

Polgár Int J Radiat Oncol Biol Phys

69:694-702; 2007.

63

ASTRO Consensus Statement APBI

Smith et al J Am Coll Surg

209:269-277; 2009

64

Results of 3D Conformal APBI

Caution needed in patient selection

Pashtan et al Int J Radiat Oncol Biol Phys

84:e271-7; 2012.

65

NSABP B-39 / RTOG 04-13

66

Smith G et al. Int J Radiat Oncol Biol Phys

88:274-84; 2014.

APBI – Nonrandomized Results

SEER subsequent mastectomy risk

Local control close enough for most patients?

DCIS

68

Breast-Conserving Surgery

How do you assess the completeness of an excision?

• Margins

• Specimen radiograph

• Post-excision pre-irradiation mammogram (PPM)

69

DCIS: Breast-Conserving Surgery + RT


Higher Lower

• Younger age Radiation

• Mode of detection Tamoxifen

• Positive margin Boost

• Large size / volume excised

• Diffuse calcifications

70

DCIS: Consistent Benefit to BCT + RT

EBCTCG

Local recurrence reduced regardless of:

• Age at diagnosis

• Extent of surgery

• Use of tamoxifen

• Method of detection

• Margin status

• Grade

• Comedonecrosis

• Architecture

• Tumor size

J Natl Cancer Inst Monogr 2010;2010:162-177

71

DCIS: Young Age - CS + XRT

Solin Int J Radiat Oncol Biol Phys 50: 991; 2001

72

DCIS: Margins - CS + XRT

Solin Int J Radiat Oncol Biol Phys 50: 991; 2001

73

DCIS: Margin Meta-analysis

4,660 patients treated with BCT+RT.

• Negative margins superior to positive margins (OR=0.36; 95% CI,

0.27- 0.47)

• Negative margins superior to close margins (OR=0.59; 95% CI, 0.42-

0.83)

• > 2 mm margins superior to <2 mm (OR 0.53, 95% CI 0.26-0.96)

• No difference in > 2 mm compared to > 5mm

Dunn et al J Clin Oncol 2009

74

DCIS: Radiation +/-Tamoxifen

A. Invasive Ipsilateral Recurrence B. DCIS Ipsilateral Recurrence

Wapnir et al. J Natl Cancer Inst 2011

75

DCIS: Boost vs. No Boost vs. No XRT

Omlin et al Lancet Oncology 1-5; 2006


with DCIS for whom we can safely omit

adjuvant radiation?

77

Breast-Conserving Surgery No RT


Higher Lower

• Younger age Tamoxifen

• Grade

• Necrosis

• Mode of detection

• Positive margin

• Diffuse calcifications

78

Van Nuys Index

Silverstein and Lagios. J Natl Cancer Inst Monogr 2010; 41:193-196

79

Harvard Study

Prospective single arm study from May 1995 – July 2002

Eligibility:• DCIS of nuclear grade 1 or 2,

necrosis noted but not excluded

• Mammogram or clinical exam with lesion ≤ 2.5cm

• Wide excision with final margins ≥ 1cm OR negative re-excision

• Radiologic confirmation that all calcifications were removed

Exclusion criteria• No Tamoxifen

Wong et al, JCO 2006 (24:1031-1036).

80

Low/Int Grade (n=565) High Grade (n=105)

10.5%

18%

ECOG E5194

• DCIS nuclear grade 1 or 2, with lesion ≤ 2.5 cm

-OR-

DCIS nuclear grade 3, with lesion ≤ 1 cm

• Wide excision with final margins ≥ 3 mm OR negative re-excision

• Radiologic confirmation that all calcifications were removed

Hughes et al, JCO 2009 (27:5319-5324).

81

RTOG 98-04 “Good Risk” DCIS

Prospective randomized trial

Eligibility

• Mammographically detected disease

• Low or intermediate nuclear grade

• <2.5 cm size

• Margins ≥ 3 mm.

• 62% had Tam - no impact on LR

Median follow-up (F/U) time was 6.46 years.

7 years Local recurrence 1% RT vs. 6% No RT

• (p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]).

McCormick et al J Clin Oncol 30, 2012

Older (>60) or reduced life expectancy

Low-Int grade – no or mimimal necrosis

ER or PR +

Margin – (at least 3 mm – 1 cm + optimal)

+/- endocrine therapy

Willing to accept modest higher local recurrence


with DCIS for whom we can safely omit

adjuvant radiation?

Indications for Postmastectomy Radiation

Risk factors for local-regional

recurrence after mastectomy

84

Case 1

45 year old woman

Clinical T2N0 Left Breast

• 3 cm tumor size

• Clinically node negative

Core biopsy positive

• invasive ductal carcinoma

• ER/PR positive, Her-2 negative

Modified radical mastectomy

Pathologic T2N2

• 3 cm invasive ductal carcinoma

• 5 of 15 positive lymph nodes

• No lymphovascular invasion

• Margins negative

High Risk Features

For Local-Regional Recurrence

≥ 4 positive axillary nodes

85

National Comprehensive Cancer Center

86

ACR Appropriateness Criteria

High Risk for Local-Regional Recurrence

87


High Risk for LRR

≥ 4 positive nodes

EBCTCG Lancet 383: 2127-2135; 2014

88

Case 2

45 year old woman


• 3 cm tumor size






Pathologic T2N0





Low Risk Features


T1-2 Tumor Size

0 positive axillary nodes

≥ 6 nodes dissected

Margins negative

89


90


Low Risk for Local-Regional Recurrence

91


Low Risk for LRR

0 positive nodes

EBCTCG Lancet 383: 2127-2135; 2014

92

Case 3

45 year old woman


• 3 cm tumor size






Pathologic T2N1





Intermediate Risk Features


T1-2 Tumor Size

1-3 positive axillary nodes


93


94


Intermediate Risk for Local-Regional Recurrence

95


Intermediate Risk for LRR

EBCTCG Lancet 383: 2127-2135; 2014

96

Mastectomy N 1-3+ Breast Cancer

10-year

Isolated

LRR (%)

1-3 Nodes

(# pts)

4-7 Nodes

(# pts)

8 + Nodes

(# pts)

T1 9 (407) 11 (180) 20 (110)

T2 7 (576) 17 (349) 20 (297)

T3 23 (35) 29 (33) 7 (29)

ECOG

Recht et al J Clin Oncol

1999;17:1689-1700.

97


Taghian et al J Clin Oncol

2004;22:4247-54.

# Isol LRR LRR+/-DF

1-3 2 1,045 6% 11%

2.1-5 1,489 10% 15%

> 5 229 8% 11%

4-9 2 512 13% 20%

2.1-5 982 15% 24%

> 5 220 20% 31%

10+ 2 187 14% 26%

2.1-5 500 20% 33%

> 5 165 20% 34%

NSABP

98


0 1-3 4-9 10

T1T2T3

61129

71229

92331

171729

11.1-22.1-33.1-44.1-5

37101326

Katz et al J Clin Oncol

18:2817-27; 2000

MDACC

99

Mastectomy N+ Breast Cancer

MDACC

Katz et al Int J Radiat Oncol Biol Phys

2001; 50:397-403.

Importance of ≥ 20%

positive nodes

100

Mastectomy N 1-3+ Breast Cancer – low risk?

Cleveland Clinic

1-3 positive nodes

Tendulkar et al Int J Radiat Oncol Biol Phys

2012; 83:e577-81.

101

Microscopic Extranodal Extension

Gruber et al J Clin Oncol

2005; 23:7089-97.

International Breast Cancer Study Group

ECE not significant for local-regional recurrence when

number of positive of nodes included in analysis

102

Mastectomy N 1-3+ Breast Cancer – low risk?

MD Anderson

T1-2, 1-3 positive nodes

Early era (1978-1997) vs. later era (2000-2007)

Early era 5-year 9.5% without PMRT and 3.4% with PMRT

Late era 5-year 2.8% without PMRT and 4.2% with PMRT

McBride et al Int J Radiat Oncol Biol Phys

89:392-8; 2014

103

Young Age

Age # Isol LRR LRR+/-DF

20-39 1130 15% 26%

40-49 2050 13% 21%

50-59 1600 11% 17%

60+ 978 10% 14%

p=0.13 p<0.0001

Significant on Multivariate Analysis

NSABP

Node Positive Breast Cancer

Taghian et al J Clin Oncol

2004;22:4247-54.

104

Lymphovascular Invasion& Positive Nodes

Matsunuma et al Int J Radiat Oncol Biol

Phys 2012;83: 845-52.

105

Case 4

45 year old woman


• 6 cm tumor size






Pathologic T3N0





Risk of Local-Regional Recurrence

Various Data

T3 Tumor Size



No Lymphovascular Invasion

Negative Margin

No Very Young Age

106


107

Mastectomy for T3N0 Breast Cancer

NSABP

Isolated LRF 7%

Taghian J Clin Oncol

2006;24:3927-32.

108

Mastectomy for T3N0 Breast Cancer

7.6%

21%

Floyd et al Int J Radiat Oncol Biol Phys

2006;66:358-64.

MGH, Harvard, MD Anderson, Yale

Importance of LVI

109


Risk for Local-Regional Recurrence?

110

Case 5

45 year old woman


• 3 cm tumor size






Pathologic T2N0




• Margins positive

Intermediate Risk Features


T1-2 Tumor Size



Positive Margins

111


112

Close/Positive Margins

MGH, Harvard

Node negative women

Jagsi et al Int J Radiat Oncol Biol Phys

2005; 62:1035-9.

113

Close/Positive Margins

Brigham & Women’s Hospital and Dana-Farber

Positive margin

• + LVI = 27%

• + grade 3 = 13%

• + triple - = 33%

Childs et al Int J Radiat Oncol Biol Phys

84:1133-8; 2012

114


Intermediate Risk for Local-Regional Recurrence

115

4 positive axillary lymph nodes

T3 node positive tumors

T4

1-3 positive axillary nodes

T3 node negative tumors

Limited / no axillary dissection

Close / positive margins

Lymphovascular invasion

High grade

Young Age

Gross ECE

Triple Negative?

Multicentric disease?

T1 - 2

Node Negative

Margin Negative

High Risk

Definitely RT

Often RT but

not always

Intermediate

Risk

Sometimes RT

for 2-3 factors

but not always

Low Risk

No RT

Indications for PMRT

116

Molecular subtype – A Reason for PMRT?

T1-2 N0

Truong et al Int J Radiat Oncol Biol Phys

88: 57-64;2014.

Regional nodal radiation therapy

118

LEVEL I/II DISSECTION

S’Clav and Axilla

119

Supraclav and Axilla RT – 1980 to 2000

Level I-II Dissection (6+ nodes)

N-• Breast Only

• Chest Wall Only (T3,

Margin + cases)

N+• 1-3

– Breast Only (except

>20-40%+? S’clav)

– CW + S’clav

• 4+

– Breast/CW + S’clav

• No Low Axilla

– Consider for gross ECE

or >40-50% node ratio +

120

Classic Supraclavicular Field

Madu et al Radiology 221:333-9; 2001.

Meant to cover undissected Level III (infraclav) and S’clav

121

Mastectomy: Axillary Treatment

Fisher et al Surg Gyn Obstet

1981;152:765-72.

NSABP B04

Axillary RT not needed if 6+ nodes removed

122

Strom et al Int J Radiat Oncol

Biol Phys 63:1508-13; 2005.

Mastectomy: S’clav and Axillary Treatment

123


Wapnir et al J Clin Oncol 2006; 24:2028-37.

NSABP

BCS + Whole Breast RT.

2/3 1-3 + nodes, 1/3 4 or more + nodes. No Regional RT.

124


Regional node recurrence rare for N0-3 with breast RT alone.

Vicini et al Int J Radiat Oncol Biol Phys

1997; 39:1069-76.

125


BCS + Whole Breast Radiation.

No Regional Radiation.

Isolated regional node recurrences at 8 years:

• S’clav 1.3%, axilla 1.2%, infraclav 0.4% and IMN 0.3%

Galper et al Int J Radiat Oncol Biol Phys

1999; 45:1157-66.

126


Consider axillary RT for >40-50% node ratio?

Consider s’clav RT for 1-3 + and >40% node ratio?

Fortin et al Int J Radiat Oncol Biol Phys

2006; 65:33-39.

127

NO DISSECTION

S’Clav and Axilla

128

Supraclav and Axilla RT – 1980 to 2000

No Dissection or

Incomplete Dissection (≤ 5)

S’clav and Full Axilla

129

Dissection or Radiation

NSABP B-04

1159 clinically node negative patients

RM TM+ XRT TM

Node Positive 40% ? ?

1st Failure

LR 10% 5% 15%

Axillary 1% 3% 1% (18%)

Distant 30% 31% 32%

130

Dissection or Radiation

All lumpectomy + Breast Radiation

Age < 70, 3 cm size or less, cN0

Level I/II axillary dissection

• N + received RT to s’clav, IMN

• N – received RT IMN if central / medial

No Dissection

• RT included IMN and axilla

Louis-Sylvestre et al J Clin Oncol

22: 97-101; 2004.

131

Supraclav and Axilla RT – 2000 to Present

No Dissection

Average patient – should have had axillary assessment but

didn’t for some reason.

• S’clav and Low Axilla

Older, favorable patient

• High tangents Only

132

BCS + RT: Undissected Axilla

Wong 2008


No Axillary Surgery.

No Regional Radiation.

No Local-regional Recurrences.

Wong et al Int J Radiat Oncol Biol Phys

2008; 72:866-70.

133

No Axillary Dissection – Older Women

IBCSG 10-93

Women ≥ 60, cN0, ER +

Surgery + Axillary clearance + Tam vs. Surgery + Tam

J Clin Oncol 24:337-344; 2006.

134

BCS + RT: Undissected Axilla

CALGB

≥ 70

T1

Axillary node

dissection was

allowed but not

encouraged.

1/3 pN0, 2/3 cN0

RT to whole breast

and level I/II nodes

Hughes et al J Clin Oncol

31:2382-7; 2013.

135

BCS + RT: Incomplete Dissection

Regional node recurrence rare for N0-3 with breast RT alone.

Vicini et al Int J Radiat Oncol Biol Phys

1997; 39:1069-76.

136

Galper et al Int J Radiat Oncol

Biol Phys 48:125-32; 2000.

No or Incomplete Dissection – PreSentinel Node

137

Sentinel Node Biopsy

Sentinel Node Biopsy pre-2000

N0 - Treat like a negative level I/II dissection

N+ - Complete the dissection OR treat like an incomplete

dissection (Treat the s’clav and low axilla).

138

Sentinel Node Biopsy - Positive

Sentinel Node Biopsy 2000 – 2010

Resistance to completion dissection

Era of the Nomogram

If nomogram suggests low risk for additional + nodes then

may omit s’clav and axilla

• Number of + SN

• Size of + SN / micromet

• Number of – SN

• LVI

• T size

• Histology

• Etc. Etc.

139

BCS + RT: Sentinel Node Positive

ACSOG Z0011

891 patients with positive SNB

Clinical T1/T2, Clinical N0

H&E detected metastases in 1-2 nodes

No ECE

Breast tangents only

Giuliano et al JAMA

2011;305:569-75.

•Additional nodal metastases in 27% of patients

having completion node dissection.

•98% Systemic Therapy (58% chemo)

•Local-regional recurrence

3.3% without completion dissection

4.3% with completion dissection

P=0.28

140


ACSOG Z0011

Breast tangents only?

• 15% s’clav RT

• 50% high tangents

•Additional nodal metastases in 27% of patients

having completion node dissection.

•98% Systemic Therapy (58% chemo)

•Local-regional recurrence

3.3% without completion dissection

4.3% with completion dissection

P=0.28

Jagsi et al J Clin Oncol

32: 3600-06; 2014.

141


IBCSG 23–01

Axillary dissection versus no axillary dissection in patients

with sentinel-node micrometastases

931 patients (10% mastectomy)

Galimberti et al Lancet Oncol

2013; 14: 297–305.

142


EORTC AMAROS trial

Radiotherapy or surgery of the axilla after a positive SN

• 12% mastectomy

All three levels of the axilla together with the medial part of the

supraclavicular fossa were considered clinical target volume.

The prescribed dose to the axilla was 50 Gy in 25 fractions.

Postoperative axillary irradiation in patients undergoing ALND

was allowed in patients with four or more tumor-positive

nodes (pN2 or pN3).

5-year axillary recurrence rate after a positive SNB was

• 0.54% (4/744) after ALND

• 1.03% (7/681) after ART

Rutgers et al ASCO 2013.

143

Sentinel Node Biopsy

Sentinel Node Biopsy post Z0011

N0 - Treat like a negative level I/II dissection

N+ - Patient selection / judgment needed

• Option A: Complete the dissection – will it affect systemic therapy?

• Option B: Treat like an incomplete dissection

– Treat the s’clav and low axilla

– AMAROS

• Option C: Treat a high tangent or a normal tangent

– Z0011 / IBCSG

144

IMN

145

IMN Treatment

Clinical IMN Recurrence is Exceedingly Low

Incidence of IMN positivity is Low

• High in old series of advanced breast cancer

• Much lower in modern series

Randomized Trials of IMN Treatment

• Negative or <1-2% survival benefit

What is the added cost in toxicity of treatment?

• Cardiac effects

146

Clinical IMN Recurrence - Mastectomy

JCO 17: 1689-

1700; 1999

Any IMN?

Recht et al J Clin Oncol

17: 1689-1700;1999.

147

Clinical IMN Recurrence - Lumpectomy


No Regional Radiation

Galper et al Int J Radiat Oncol Biol Phys

1999; 45:1157-66.

148

Extended Radical Mastectomy – Old Data

IMN positive (%)

Axilla Negative Axilla Positive

Series # Inner Central Outer Total Inner Central Outer Total

Cáceres 600 -- -- -- 7 44 33 19 29

Donegan 113 12 0 4 6 54 29 31 34

Handley 1000 12 7 4 8 50 46 22 35

Lacour et al. 703 11 8 9 37 22 28

Livingston and Arlen 583 14 10 5 8 59 43 23 32

Sugg 292 -- -- -- 5 -- -- -- 44

Urban and Marjani 725 13 6 3 8 65 48 42 52

Veronesi et al. 1085 -- -- -- 9 -- -- -- 28

< 10% 30%

149

Sentinel Node Studies

Hindie et al Int J Radiat Oncol Biol Phys 83:

1081-8; 2012.

Review of 6 prospective studies of SNB and IMN

Modern incidence of + IMN is likely <5%

150

IMN Irradiation – Old Negative Studies

Radical Mastectomy Radical Mastectomy

Series # + IMN irradiation* # Alone Follow-up

DM OS DM OS

Fisher et al. 470 40% 56% 633 32% 62% 5 years

P=NS

Høst et al.

Stage I 170 -- 60% 186 -- 70% 15 years

P=0.08

Stage II 95 34%† 42% 91 50%† 44% 15 years

P=NS P=0.15 † 10 years

Palmer & Ribeiro

Node - 139 -- 16% 142 -- 26% 30 years

P=0.13

Node + 243 -- 8% 217 -- 8% 30 years

P=0.7

Arriagada 41‡ 51% 59% 31‡ 35% 74% 15 yr crude

P=0.22 p=0.29

Veronesi 23‡ -- 48% (DFS) 23‡ -- 68% (DFS) 10 years

P=NS

* Includes supraclavicular +/- axillary irradiation

‡ Includes patients treated with lumpectomy and breast radiation

151

Randomized Trial IMN Radiation

DBCG-IMN study

3,000 + Node positive

• Right breast – IMN RT

• Left breast – no IMN RT

Median follow up of seven years.

OS 78% versus 75% in favor of IMN radiotherapy.

• HR=0.86 (95% CI (0.75; 0.99), p=0.04.

Thorsen et al, ESTRO Vienna 2013.

152

Randomized Trial IMN Radiation

French Study

Mastectomy and N + or central/medial tumors.

All patients received postoperative irradiation of the chest wall

and supraclavicular nodes.

Randomly assigned to receive IMN irradiation or not.

Hennequin et al Int J Radiat Oncol Biol Phys

86: 860-6; 2013.

153

Randomized Trial IMN / Sclav Irradiation

NCIC CTG MA.20 2000-2007 with median 62 months follow-up

1832 patients with high risk node negative (T3) or node

positive breast cancer.

1-3+ Nodes 85%

OS 92.3% vs 90.7% (HR .76, p = .07)

LR DFS 96.8% vs 94.5% (HR .59, p=.02)

DFS 89.7% vs 84 % (HR .68, p = .003) Whelan et al

ASCO 2011

154

Randomized Trial IMN / Sclav Irradiation

EORTC trial 22922-10925

Axillary lymph node involvement and/or a centrally or medially

located tumour.

4,004 patients (76% BCT)

OS at 10 years was 82.3% with and 80.7% without radiation

therapy to the internal mammary and medial supraclavicular

lymph nodes

• (HR=0.87 (95%CI: 0.76, 1.00), Logrank p=0.056).

Poortmans et al, ESTRO Vienna 2013.

155

IMN / Sclav Irradiation

Could all benefit be from the s’clav/axillary treatment?

Budach et al Radiat Oncol 8: 267; 2013.

156


Is IMN RT benefit from underestimated incidence that never become

apparent local recurrence? Or all from the S’clav?

IMN benefit in absence of local control doesn’t fit the EBCTCG model!

Lancet 2005;

366: 2087–2106.

Radiation after

neoadjuvant chemotherapy

158

Mechanism of Increased Breast-Conserving Surgery after

Neoadjuvant Chemotherapy

Pre-chemo Volume

Post-chemo

Volume?

Decrease in clinical tumor size.

More favorable ratio of tumor to

breast size.

159

NSABP B-18 Breast Conservation

IBTR (%) as site of 1st treatment failurePostop Preop

# Chemo # Chemo448 7.6 503 10.7 p=0.12

Downstaged Lump initially

# to lump # proposed

69 15.9 434 9.9 p=0.04

Wolmark et al J Natl Cancer Inst Monogr

2001;30:96-102.

Modest increase in breast conservation

Modest increase in local recurrence in downstaged patients

160

Breast Conservation after Neoadjuvant Chemotherapy

NSABP B-18 and B-27

Breast-conserving surgery and whole breast radiation

No regional nodal radiation

Mamounas et al J Clin Oncol

2012;30:3960-6.

Add Sclav RT

for ypN+

?Add a boost

161

Neoadjuvant Chemotherapy and Mastectomy

Buchholtz et al J Clin Oncol

2002;20:17-23.

MDACC

Generally cT3 or pN+ indications for PMRT

162

Neoadjuvant Chemotherapy and Mastectomy

NSABP B-18 and B-27

No postmastectomy radiation

Mamounas et al J Clin Oncol

2012;30:3960-6.

RT for pN+

?cN+ and ypN-

need more data

163

NSABP B-51/RTOG 1304: pN1 to ypN0

Radiation therapy for inflammatory

breast cancer

165

Inflammatory LABC

Clinical findings:

• Rapid onset

• Edema, redness, skin changes

• Peau D’orange > 1/3 of the breast.

Clinical diagnosis of inflammatory BUT pathology is needed!

• Core biopsy of a node

• Skin punch biopsy

• Breast incisional biopsy

Dermal lymphatic invasion is not required for diagnosis.

Not the same as locally advanced neglected cancer.

166

Management of Inflammatory LABC

Neoadjuvant Chemotherapy

Second Line Chemotherapy if < cCR

Preop Radiation if < cCR


Endocrine Therapy (if ER/PR+)

Postmastectomy radiation

167

Inflammatory LABC – Breast Conservation

168

Inflammatory LABC

Harris et al Int J Radiat Oncol Biol Phys

2003;55:1200-8.

CW / Breast 50 Gy

Bolus

Supraclav in all

Axilla in most

IMN in few

PENN

169

Inflammatory LABC

MDACC

Dose escalation for < partial chemotherapy response,

close/positive margins, and age < 45 years

Bristol et al Int J Radiat Oncol Biol Phys

2008;72:474-84.

CW 50 Gy + 10 Gy Boost or

51 Gy BID + 15 Gy Boost

Comprehensive nodal RT

170

Inflammatory LABC

MSKCC

Damast et al Int J Radiat Oncol Biol Phys

2010;77:1105-12.

CW 5,040 Gy Bolus Daily

Thank you

The End!

Gary M. Freedman, M.D.

Associate Professor

Documents

The Management of Breast Cancer · PDF file5 Models of Breast Cancer Halstedian 1900 –1970’s A local-regional disease Justification for more radical surgery / radiation Fisher