Download The Management of Breast Cancer - American Society for Radiation

The Management of Breast Cancer
2015 ASTRO Spring Refresher
Gary M. Freedman, M.D.
Associate Professor
Disclosure
 I have no conflicts of interest to disclose.
2
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.
3
Introduction
Local Therapy and Survival in Breast Cancer
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
5
NSABP B-04
 “3 Levels” of Axillary Treatment (including regional node RT)
 No differences in survival
Fisher et al NEJM 347: 567-75; 2002.
6
NSABP B-06
 “3 Levels” of Breast Treatment
 RT recommended for breast conservation not survival
Fisher et al N Engl J Med 2002; 347:1233-41.
7
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
8
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?
WHY GIVE PMRT? JUST LOCAL CONTROL FOR LOCALLY
ADVANCED OR INFLAMMATORY CASES?
WHY CARE ABOUT LUMPECTOMY MARGINS?
9
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.
10
The Spectrum Model
T
I
M
E
Not every local recurrence prevented improves survival – but some do.
Primary
Treatment
RT
RT
No
Failure
Local
Failure
Prevent
This!
Alive
Distant
Failure
Local
and
Distant
Failure
Distant
Failure
Dead
(Early)
Dead
(Late)
11
PMRT – 1st failures are not the whole story
MRM ± radiation
Node positive patients after 15 years
No chemotherapy/endocrine therapy
No XRT
XRT
First Failure
Local Failure
37%
10%
Distant Metastases
34%
43%
Total Failure
Local Failure
56%
19%
Distant Metastases
72%
54%
Death
70%
61%
Difference
- 27%
+ 9%
- 18%
- 9%
Arriagada et al. JCO 13:2869 1995
12
Early Breast Cancer Trialists’ Collaborative Group
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.
Lancet 2005; 366: 2087–2106
13
Local Control Benefit Predicts the Late Survival Benefit
No LC 
No Surv 
Big LC 
Big Surv 
EBCTCG Lancet 383: 2127-2135; 2014
14
T1-T2 Invasive Breast Cancer
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
16
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
17
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.
18
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.
19
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.
20
BCS + RT Invasive Breast Cancer
 Factors associated with local recurrence
 Higher
• Positive margin
• Young age
• Subtype
Lower
Boost
Systemic Therapy
21
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.
22
Re-excision of Margins
American College of Radiology
Invasive Breast Cancer
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.
23
Local Recurrence By Age - Then
Bartelink et al J Clin Oncol
25: 3259-3265; 2007.
24
Young Age – Now
 Today the age effect is much diminished
 Selection Factors: BRCA, Imaging
 Treatment Factos: Margins, Systemic Therapy, Boost
Arvold et al J Clin Oncol
29:3885-3891; 2011.
25
BCS + RT by Subtype
Hattangadi-Gluth et al Int J Radiat Oncol
Biol Phys 82: 1185-91; 2012.
26
Young Age – Biology
 Adjusting for biology now the age effect is much diminished
 Margins – not significant?
Predictor
Age, years
BC subtype
Luminal A
AHR
0.97
1 (reference)
95% CI
0.94 to 0.99
P
.009
—
—
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
WB dose, Gy
1.32
0.91
0.96 to 1.80
0.86 to 0.98
.08
.007
Arvold et al J Clin Oncol
29:3885-3891; 2011.
27
Young Age – Biology
 Adjusting for biology now the age effect is much diminished
Demerci et al Int J Radiat Oncol Biol Phys
83: 814-820; 2012.
28
Survival is equal …
But is it still the case that local control is better with
Mastectomy versus BCS + RT?
LOCAL CONTROL TODAY
29
BCS + RT: Node Positive
 NSABP
 BCS + Whole Breast Radiation. No Boost.
Wapnir et al J Clin Oncol 2006; 24:2028-37.
30
BCS + Hypofractionated Radiation
UK START B
Haviland et al Lancet Oncol 2014; 14:1086-94.
31
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.
32
BCS + RT vs. Mastectomy
 T1-2 N0 triple negative
Abdulkarim et al J Clin Oncol
29:2852-2858; 2011.
33
BCS + RT vs. Mastectomy
 T1-2 N0 triple negative
Zumsteg et al Ann Surg Oncol
20:3469–3476; 2013
34
Are there any subgroups of patients
with T1 for whom we can safely omit
adjuvant radiation?
Local Control Benefit Predicts the Late Survival Benefit
EBCTCG Lancet 378:771-84; 2011.
36
EBCTCG – BCS +/- RT
 No subgroup without
a benefit from RT
37
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.
38
PRIME II




Age 65 or older
Hormone-positive
Low-grade
Node negative
 5-year IBTR 4.1% vs. 1.3%
San Antonio 2013
39
Are there any subgroups of patients
with T1 for whom we can safely omit
adjuvant radiation?
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
Shortening Postlumpectomy Radiation
‘‘Modern” Trials – Pre 2002!
WHOLE BREAST
HYPOFRACTIONATION
RESULTS
42
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
749
50/25
60
6.7
750
41.6/13
61
5.6
737
39/13
61
8.1
1105
50/25
41
5.2
1110
40/15
44
3.8
612
50/25
0
6.7
622
42.5/16
0
6.2
START A
START B
OCOG
1998-2002
1999-2001
1993-1996
10 Years
10 Years
10 Years
RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre
START: Standardization of Breast Radiotherapy
OCOG: Ontario Clinical Oncology Group
43
OCOG Randomized Trial
42.5 Gy 50 Gy
Cosmesis gd/exc
70%
71%
Whelan et al N Engl J Med
Whelan et al
362:513-20; 2010.
N Engl J Med 362:513-20; 2010
44
UK START A/B Cosmetic Outcomes
Haviland et al Lancet Oncol
2014; 14:1086-94.
45
ASTRO Consensus Conference
 Hypofractionated WBI was
 My Guidelines
suitable outside of a clinical trial
• DCIS or invasive
• Node positive or node negative
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
•
•
•
Any age
Any chemo
Sequential boost allowed
 Avoid hypofractionation for
•
•
Large dose inhomogeneity
Regional node irradiation
 The task force did not reach
consensus on hypofractionated
WBI when a tumor bed boost
was thought to be indicated.
Smith et al
Int J Radiat Oncol Biol Phys 2011.
46
2D Planning 80-90’s – Wedged Tangent
 Central axis contour.
 Goal of 10% or lower
dose inhomogeneity.
 Off-axis inhomogeneity
even higher.
Chest Wall/Lung
Prescription
Point
47
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
48
Modern Volume-Based 3D Planning
 PTV and PTVeval Structures
49
Volume Based Forward Planning
 3D Conformal Field in Field Forward Planning
50
Volume Based Inverse Planning
 IMRT Inverse Planning – Sliding Window
51
Isodose Distribution
Same DVH Goals for
3D or IMRT:
 PTVeval 95% > 95%
 V105 < 10%
 V110 = 0%
52
RTOG 1005
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
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
R
A
N
D
O
M
I
Z
E
ARM 1: Standard fractionation
Whole Breast 50 Gy / 25 fractions / 2.0 Gy daily
Optional fractionation of 42.7 Gy in 16 fractions permissible
Sequential Boost 12 Gy /6 fractions /2.0 Gy daily or
14.0 Gy /7 fractions /2 Gy daily
ARM 2: Hypofractionation (15 fractions total)
Whole Breast 40 Gy/15 fractions/2.67 Gy daily
Concurrent boost 48.0 Gy/3.2 Gy daily
53
Accelerated Partial Breast Irradiation
APBI
54
Intracavitary Balloon Catheter Radiation
 Simplest dosimetry.
 Treats 1-2 cm around lumpectomy cavity.
 Less operator skill dependent.
Watch for
tissue conformance
skin distance
Arthur and Vicini J Clin Oncol 23:172635; 2005.
RTOG 04-13 / NSABP B-39
55
MammoSite Registry
 1,449 cases
 Local recurrence
Shah et al Ann Surg Oncol
20:3279–3285; 2013
56
Complications in Catheter APBI









Device removal
Catheter leak
Catheter rupture
Infection
Seroma
Skin toxicity
Fat Necrosis
Fibrosis
Telangiectasia
57
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
58
Results of 3D Conformal APBI
Vera et al Practical Rad Onc 4:147-52; 2014.
59
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.
60
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
DHI = Dose Homogeneity Index
Wazer et al Int J Radiat Oncol Biol Phys
64: 489-495; 2006.
61
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.
62
ASTRO Consensus Statement APBI
Smith et al J Am Coll Surg
209:269-277; 2009
63
Results of 3D Conformal APBI
 Caution needed in patient selection
Pashtan et al Int J Radiat Oncol Biol Phys
84:e271-7; 2012.
64
NSABP B-39 / RTOG 04-13
65
APBI – Nonrandomized Results
 SEER subsequent mastectomy risk
 Local control close enough for most patients?
Smith G et al. Int J Radiat Oncol Biol Phys
88:274-84; 2014.
66
DCIS
Breast-Conserving Surgery
 How do you assess the completeness of an excision?
• Margins
• Specimen radiograph
• Post-excision pre-irradiation mammogram (PPM)
68
DCIS: Breast-Conserving Surgery + RT
 Factors associated with local recurrence
 Higher
•
•
•
•
•
Younger age
Mode of detection
Positive margin
Large size / volume excised
Diffuse calcifications
Lower
Radiation
Tamoxifen
Boost
69
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
70
DCIS: Young Age - CS + XRT
Solin Int J Radiat Oncol Biol Phys 50: 991; 2001
71
DCIS: Margins - CS + XRT
Solin Int J Radiat Oncol Biol Phys 50: 991; 2001
72
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, 0.420.83)
• > 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
73
DCIS: Radiation +/-Tamoxifen
A. Invasive Ipsilateral Recurrence
B. DCIS Ipsilateral Recurrence
Wapnir et al. J Natl Cancer Inst 2011
74
DCIS: Boost vs. No Boost vs. No XRT
Omlin et al Lancet Oncology 1-5; 2006
75
Are there any subgroups of patients
with DCIS for whom we can safely omit
adjuvant radiation?
Breast-Conserving Surgery No RT
 Factors associated with local recurrence
 Higher
•
•
•
•
•
•
Younger age
Grade
Necrosis
Mode of detection
Positive margin
Diffuse calcifications
Lower
Tamoxifen
77
Van Nuys Index
Silverstein and Lagios. J Natl Cancer Inst Monogr 2010; 41:193-196
78
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).
79
ECOG E5194
Low/Int Grade (n=565)
High Grade (n=105)
18%
10.5%
• DCIS nuclear grade 1 or 2, with lesion ≤ 2.5 cm
-ORDCIS 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).
80
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
81
Are there any subgroups of patients
with DCIS for whom we can safely omit
adjuvant radiation?
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
Risk factors for local-regional
recurrence after mastectomy
Indications for Postmastectomy Radiation
Case 1
 45 year old woman
 Clinical T2N0 Left Breast
• 3 cm tumor size
• Clinically node negative
 Core biopsy positive
High Risk Features
For Local-Regional Recurrence
≥ 4 positive axillary nodes
• 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
84
National Comprehensive Cancer Center
85
ACR Appropriateness Criteria
 High Risk for Local-Regional Recurrence
86
Early Breast Cancer Trialists’ Collaborative Group
 High Risk for LRR
 ≥ 4 positive nodes
EBCTCG Lancet 383: 2127-2135; 2014
87
Case 2
 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 T2N0
•
•
•
•
Low Risk Features
For Local-Regional Recurrence
T1-2 Tumor Size
0 positive axillary nodes
≥ 6 nodes dissected
Margins negative
3 cm invasive ductal carcinoma
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative
88
National Comprehensive Cancer Center
89
ACR Appropriateness Criteria
 Low Risk for Local-Regional Recurrence
90
Early Breast Cancer Trialists’ Collaborative Group
 Low Risk for LRR
 0 positive nodes
EBCTCG Lancet 383: 2127-2135; 2014
91
Case 3
 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
Intermediate Risk Features
For Local-Regional Recurrence
T1-2 Tumor Size
1-3 positive axillary nodes
≥ 6 nodes dissected
 Modified radical mastectomy
 Pathologic T2N1
•
•
•
•
3 cm invasive ductal carcinoma
2 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative
92
National Comprehensive Cancer Center
93
ACR Appropriateness Criteria
 Intermediate Risk for Local-Regional Recurrence
94
Early Breast Cancer Trialists’ Collaborative Group
 Intermediate Risk for LRR
EBCTCG Lancet 383: 2127-2135; 2014
95
Mastectomy N 1-3+ Breast Cancer
 ECOG
10-year
Isolated
LRR (%)
T1
1-3 Nodes
(# pts)
4-7 Nodes
(# pts)
8 + Nodes
(# pts)
9 (407)
11 (180)
20 (110)
T2
7 (576)
17 (349)
20 (297)
T3
23 (35)
29 (33)
7 (29)
Recht et al J Clin Oncol
1999;17:1689-1700.
96
Mastectomy N 1-3+ Breast Cancer
 NSABP
1-3  2
2.1-5
>5
#
1,045
1,489
229
Isol LRR LRR+/-DF
6%
11%
10%
15%
8%
11%
4-9  2
2.1-5
>5
512
982
220
13%
15%
20%
20%
24%
31%
10+  2
2.1-5
>5
187
500
165
14%
20%
20%
26%
33%
34%
Taghian et al J Clin Oncol
2004;22:4247-54.
97
Mastectomy N 1-3+ Breast Cancer
 MDACC
T1
T2
T3
1
1.1-2
2.1-3
3.1-4
4.1-5
0
1-3
4-9
10
6
11
29
7
12
29
9
23
31
17
17
29
3
7
10
13
26
Katz et al J Clin Oncol
18:2817-27; 2000
98
Mastectomy N+ Breast Cancer
 MDACC
Importance of ≥ 20%
positive nodes
Katz et al Int J Radiat Oncol Biol Phys
2001; 50:397-403.
99
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.
100
Microscopic Extranodal Extension
 International Breast Cancer Study Group
 ECE not significant for local-regional recurrence when
number of positive of nodes included in analysis
Gruber et al J Clin Oncol
2005; 23:7089-97.
101
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
102
Young Age
 NSABP
 Node Positive Breast Cancer
Age
20-39
40-49
50-59
60+
#
1130
2050
1600
978
Isol LRR
15%
13%
11%
10%
p=0.13
LRR+/-DF
26%
21%
17%
14%
p<0.0001
Significant on Multivariate Analysis
Taghian et al J Clin Oncol
2004;22:4247-54.
103
Lymphovascular Invasion& Positive Nodes
Matsunuma et al Int J Radiat Oncol Biol
Phys 2012;83: 845-52.
104
Case 4
 45 year old woman
 Clinical T3N0 Left Breast
• 6 cm tumor size
• Clinically node negative
 Core biopsy positive
• invasive ductal carcinoma
• ER/PR positive, Her-2 negative
 Modified radical mastectomy
 Pathologic T3N0
•
•
•
•
6 cm invasive ductal carcinoma
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins negative
Risk of Local-Regional Recurrence
Various Data
T3 Tumor Size
0 positive axillary nodes
≥ 6 nodes dissected
No Lymphovascular Invasion
Negative Margin
No Very Young Age
105
National Comprehensive Cancer Center
106
Mastectomy for T3N0 Breast Cancer
 NSABP
 Isolated LRF 7%
Taghian J Clin Oncol
2006;24:3927-32.
107
Mastectomy for T3N0 Breast Cancer
 MGH, Harvard, MD Anderson, Yale
 Importance of LVI
21%
7.6%
Floyd et al Int J Radiat Oncol Biol Phys
2006;66:358-64.
108
ACR Appropriateness Criteria
 Risk for Local-Regional Recurrence?
109
Case 5
 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 T2N0
•
•
•
•
Intermediate Risk Features
For Local-Regional Recurrence
T1-2 Tumor Size
0 positive axillary nodes
≥ 6 nodes dissected
Positive Margins
3 cm invasive ductal carcinoma
0 of 15 positive lymph nodes
No lymphovascular invasion
Margins positive
110
National Comprehensive Cancer Center
111
Close/Positive Margins
 MGH, Harvard
 Node negative women
Jagsi et al Int J Radiat Oncol Biol Phys
2005; 62:1035-9.
112
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
113
ACR Appropriateness Criteria
 Intermediate Risk for Local-Regional Recurrence
114
Indications for PMRT
 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
115
Molecular subtype – A Reason for PMRT?
 T1-2 N0
Truong et al Int J Radiat Oncol Biol Phys
88: 57-64;2014.
116
Regional nodal radiation therapy
S’Clav and Axilla
LEVEL I/II DISSECTION
118
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 +
119
Classic Supraclavicular Field
 Meant to cover undissected Level III (infraclav) and S’clav
Madu et al Radiology 221:333-9; 2001.
120
Mastectomy: Axillary Treatment
 NSABP B04
 Axillary RT not needed if 6+ nodes removed
Fisher et al Surg Gyn Obstet
1981;152:765-72.
121
Mastectomy: S’clav and Axillary Treatment
Strom et al Int J Radiat Oncol
Biol Phys 63:1508-13; 2005.
122
BCS + RT: Node Positive
 NSABP
 BCS + Whole Breast RT.
 2/3 1-3 + nodes, 1/3 4 or more + nodes. No Regional RT.
Wapnir et al J Clin Oncol 2006; 24:2028-37.
123
BCS + RT: Node Positive
 Regional node recurrence rare for N0-3 with breast RT alone.
Vicini et al Int J Radiat Oncol Biol Phys
1997; 39:1069-76.
124
BCS + RT: Node Positive
 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.
125
BCS + RT: Node Positive
 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.
126
S’Clav and Axilla
NO DISSECTION
127
Supraclav and Axilla RT – 1980 to 2000
No Dissection or
Incomplete Dissection (≤ 5)
 S’clav and Full Axilla
128
Dissection or Radiation
 NSABP B-04
 1159 clinically node negative patients
Node Positive
1st Failure
LR
Axillary
Distant
RM
40%
TM+ XRT
?
TM
?
10%
1%
30%
5%
3%
31%
15%
1% (18%)
32%
129
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.
130
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
131
BCS + RT: Undissected Axilla





Wong 2008
BCS + Whole Breast Radiation.
No Axillary Surgery.
No Regional Radiation.
No Local-regional Recurrences.
Wong et al Int J Radiat Oncol Biol Phys
2008; 72:866-70.
132
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.
133
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.
134
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.
135
No or Incomplete Dissection – PreSentinel Node
Galper et al Int J Radiat Oncol
Biol Phys 48:125-32; 2000.
136
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).
137
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.
138
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
•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
Giuliano et al JAMA
2011;305:569-75.
139
BCS + RT: Sentinel Node Positive
 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.
140
BCS + RT: Sentinel Node Positive
 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.
141
BCS + RT: Sentinel Node Positive
 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.
142
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
143
IMN
144
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
145
Clinical IMN Recurrence - Mastectomy
Any IMN?
Recht et al J Clin Oncol
JCO 17: 168917: 1689-1700;1999.
1700; 1999
146
Clinical IMN Recurrence - Lumpectomy
 BCS + Whole Breast Radiation.
 No Regional Radiation
Galper et al Int J Radiat Oncol Biol Phys
1999; 45:1157-66.
147
Extended Radical Mastectomy – Old Data
IMN positive (%)
Axilla Negative
Series
#
Inner Central Outer
Axilla Positive
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
8
9
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
11
< 10%
37
30%
148
Sentinel Node Studies
 Review of 6 prospective studies of SNB and IMN
 Modern incidence of + IMN is likely <5%
Hindie et al Int J Radiat Oncol Biol Phys 83:
1081-8; 2012.
149
IMN Irradiation – Old Negative Studies
Radical Mastectomy
Alone
#
OS
DM
62%
633 32%
P=NS
Fisher et al.
Radical Mastectomy
# + IMN irradiation*
OS
DM
56%
40%
470
Høst et al.
Stage I
170
--
60%
186
--
Stage II
95
34%†
42%
91
50%†
P=NS
139
--
16%
142
--
243
--
8%
217
--
Arriagada
41‡
51%
59%
31‡
Veronesi
23‡
--
48% (DFS)
Series
Palmer & Ribeiro
Node Node +
35%
P=0.22
-23‡
Follow-up
5 years
70%
P=0.08
44%
P=0.15
15 years
26%
P=0.13
8%
P=0.7
74%
p=0.29
68% (DFS)
P=NS
30 years
15 years
† 10 years
30 years
15 yr crude
10 years
* Includes supraclavicular +/- axillary irradiation
‡ Includes patients treated with lumpectomy and breast radiation
150
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.
151
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.
152
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
153
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.
154
IMN / Sclav Irradiation
 Could all benefit be from the s’clav/axillary treatment?
Budach et al Radiat Oncol 8: 267; 2013.
155
Early Breast Cancer Trialists’ Collaborative Group
 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.
156
Radiation after
neoadjuvant chemotherapy
Mechanism of Increased Breast-Conserving Surgery after
Neoadjuvant Chemotherapy
 Decrease in clinical tumor size.
 More favorable ratio of tumor to
breast size.
Post-chemo
Volume?
Pre-chemo Volume
158
NSABP B-18 Breast Conservation
 Modest increase in breast conservation
 Modest increase in local recurrence in downstaged patients
IBTR (%) as site of 1st treatment failure
Postop
Preop
#
Chemo
#
Chemo
448
7.6
503
10.7
#
69
Downstaged
to lump
15.9
#
434
p=0.12
Lump initially
proposed
9.9
p=0.04
Wolmark et al J Natl Cancer Inst Monogr
2001;30:96-102.
159
Breast Conservation after Neoadjuvant Chemotherapy
 NSABP B-18 and B-27
?Add a boost
 Breast-conserving surgery and whole breast radiation
 No regional nodal radiation
Add Sclav RT
for ypN+
Mamounas et al J Clin Oncol
2012;30:3960-6.
160
Neoadjuvant Chemotherapy and Mastectomy
 MDACC
 Generally cT3 or pN+ indications for PMRT
Buchholtz et al J Clin Oncol
2002;20:17-23.
161
Neoadjuvant Chemotherapy and Mastectomy
 NSABP B-18 and B-27
 No postmastectomy radiation
RT for pN+
?cN+ and ypNneed more data
Mamounas et al J Clin Oncol
2012;30:3960-6.
162
NSABP B-51/RTOG 1304: pN1 to ypN0
163
Radiation therapy for inflammatory
breast cancer
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.
165
Management of Inflammatory LABC
Neoadjuvant Chemotherapy
Second Line Chemotherapy if < cCR
Preop Radiation if < cCR
Modified radical mastectomy
Endocrine Therapy (if ER/PR+)
Postmastectomy radiation
166
Inflammatory LABC – Breast Conservation
167
Inflammatory LABC
 PENN
CW / Breast 50 Gy
Bolus
Supraclav in all
Axilla in most
IMN in few
Harris et al Int J Radiat Oncol Biol Phys
2003;55:1200-8.
168
Inflammatory LABC
CW 50 Gy + 10 Gy Boost or
51 Gy BID + 15 Gy Boost
 MDACC
Comprehensive nodal RT
 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.
169
Inflammatory LABC
 MSKCC
CW 5,040 Gy Bolus Daily
Damast et al Int J Radiat Oncol Biol Phys
2010;77:1105-12.
170
The End!
Thank you
Gary M. Freedman, M.D.
Associate Professor