Radiation Therapy
in the Management of
Early Stage Breast Cancer
Jennifer L. Peterson, M.D.
Department of Radiation Oncology
Mayo Clinic, Jacksonville
No commercial interest
or off label usage
to disclose
Objectives
To discuss surgical options for early stage
breast cancer
To understand the role of radiation in the
treatment of early stage breast cancer
To demonstrate the technical aspects of
radiotherapy planning
To review the rationale and patient selection
for partial breast radiotherapy
Early Stage Breast Cancer
Early Stage
– Stage I or II
– Tumors < 5 cm in size
– Negative or 1-3 positive lymph nodes
At diagnosis
– 94% of women have tumors < 5cm
– 64% of women are node negative
Early Stage Breast Cancer
Two major treatment options
– Mastectomy
– Breast conserving therapy
Margin-negative lumpectomy
Adjuvant radiation therapy
Adjuvant therapy
– Dependent on pathologic variables
Chemotherapy
Hormonal therapy
What are the surgical
options for early stage
breast cancer?
Mastectomy
Total or simple mastectomy
– Removal of all breast tissue
Modified radical mastectomy
– Removal of breast tissue and axillary level I/II
lymph nodes
Skin sparing mastectomy
– Total or modified radical mastectomy with
preservation of the native skin through a
circumareolar incision
– Performed in conjunction with immediate
reconstruction
Mastectomy
Nipple sparing
mastectomy
– Total or modified radical
mastectomy with
preservation of the
nipple-areolar complex
– Performed in
conjunction with
immediate
reconstruction
– Controversial, not
standard of care
Courtesy of S. McLaughlin, Mayo Clinic
Nipple Sparing
Mastectomy
Nonrandomized comparison
Follow up 4.9 years
All tumors > 2cm from nipple-areolar
complex
Type of mastectomy
No. of patients
Local recurrence
MRM
134
11 (8%)
SSM
51
3 (6%)
NSM
61
3 (5%)
Gerber, et al. Ann Surg, 2003
Lumpectomy
Excision of all invasive
and noninvasive cancer
with negative margins
Definition of negative
margins varies
– NSABP definition: no
tumor at inked margin
– May vary from 1-10mm
NSABP recommends
specific types of
incisions based on
location of tumor
Indications for
Re-excision
Initial surgical procedure was less than a
complete lumpectomy
Residual calcifications on post-excision
mammogram
– 60-85% chance of detecting residual disease on
re-excision
– Increased risk of local recurrence w/o removal of
residual calcifications
– Lally, et al. Cancer 2005
9% vs. 19% local recurrence rate
Indications for
Re-excision
Positive margins
– Increased risk for local recurrence
Study
Median
Follow up
(yr)
Local Recurrence Rate per
Margin Status
Negative
Positive
Heimann, et al.
3.6
2%
11%
Gage, et al.
9.1
2%
16%
Vicini, et al.
8.5
9%
30%
Park, et al.
10.6
7%
18%
Dibase, et al
4.3
12%
33%
Surgical Management of
Lymph Nodes
Surgical evaluation is a important component of
pathological staging
– 30% of clinically node negative pts. have + nodes
pathologically
Historically, axillary dissection was part of standard
surgery
Currently, sentinel lymph node biopsy eliminates
need for axillary dissection in biopsy negative
patients
In patients with positive sentinel lymph node
biopsy, completion axillary dissection is
recommended
– Defines prognosis
– Decreases risk of axillary recurrence
Sentinel Lymph Node
Biopsy
Technetium-99 sulfur
colloid and/or blue dye
injected into breast
skin or tissue
surrounding tumor
Intraoperative cytology
to determine status
NSABP B32
– SLNB alone vs.
SLNB/ALND
– 10% false negative rate
– 97% accuracy
Krag, et al. Lancet Oncol 2007
Lumpectomy or
Mastectomy?
How do you determine the
best approach?
NSABP B6 Trial
Stage I or II
Breast Cancer
1,851 pts.
Total
Mastectomy
589 pts.
Lumpectomy
634 pts.
Lumpectomy
+Radiation
628 pts.
Tumor size < 4cm
Axillary lymph node dissection performed in all pts.
Negative margins – no tumor at inked margin
Radiation included 50Gy to whole breast
Fisher, et al. NEJM 2002
NSABP B6 Trial
Outcomes at 20 years
TM
L
L + XRT
Ipsilateral breast
recurrence
NA
39.2%
14.3%
Local recurrence
after mastectomy
10.2%
NA
NA
Disease free survival
36%
35%
35%
Overall Survival
47%
46%
46%
Fisher, et al. NEJM 2002
Randomized Trials of Mastectomy
vs. Breast Conserving Therapy
Study
No. of
patients
Stage
Follow
up (yrs)
Local Recurrence (%)
NSABP
B6
1,219
I or II
20
10
14
French
179
I
15
14
9
Milan
701
I
20
2
9
NCI
237
I or II
18
6
22
EORTC
874
I or II
10
12
20
Danish
904
I,II, or
III
6
4
3
Mastectomy Lumpectomy
+ XRT
Breast Conservation
Rates by Country
France - 72%
UK - 69%
Italy - 59%
Germany - 57%
USA - 44%
Spain - 34%
Poland - 2%
Cosmetic Outcome
Courtesy of L. Vallow, Mayo Clinic
Cosmetic Outcome
Courtesy of L. Vallow, Mayo Clinic
Barriers to Breast
Conservation
Stage at diagnosis
Lack of screening
Physician and patient attitudes
Access to radiotherapy
Indications for
Mastectomy
Multicentric disease
Anticipated poor cosmetic outcome with
lumpectomy
Persistent positive margins
Diffuse microcalcifications
Contraindications to radiation therapy
–
–
–
Pregnancy
Collagen vascular disease
Prior radiation therapy
Is adjuvant radiation
always indicated after
lumpectomy?
Randomized Trials of Lumpectomy
vs. Lumpectomy + Radiation
Study
No. of
patients
Tumor
size/
Node
status
Follo
w up
(yrs)
NSABP
B6
1,262
<4cm,
NN/NP
Veronesi
et al.
579
Clark et
al.
Fyles et
al.
Local Recurrence (%)
Lumpectomy
Lumpectomy
+ XRT
20
39.2
14.3
<2.5cm,
NN/NP
10
23.5
5.8
837
<4cm,
NN
7.6
35
11
769
<5cm,
NN
7.8
12.2
4.1
Early Breast Cancer Trialists
Collaborative Group
Meta-analysis of trials comparing
radiation vs. no radiation after BCS
– 7,300 patients
– 5 year risk of local recurrence
7% with XRT vs. 26% w/o XRT
19% absolute reduction
– 5.4% absolute reduction in breast cancer
mortality
Clark et al., Lancet 2005
Prognostic Factors for Local
Recurrence after BCT
Perez et al. Principles and Practice of Radiation Oncology, 5th ed.
NSABP B21
Tumor size < 1cm
1,009 pts.
Tamoxifen
336 pts.
XRT + placebo
336 pts.
XRT + tamoxifen
337 pts.
All pts. underwent lumpectomy and axillary
lymph node dissection
– Node negative, no tumor at inked margin
Follow up 7.2 years
Fisher, et al. JCO 2002
NSABP B21
Incidence of local relapse at 8 years
– Tamoxifen group: 16.5%
– XRT group: 9.3%
– XRT + tamoxifen group: 2.8%
Overall survival
– 93% both arms
Fisher, et al. JCO 2002
CALGB Trial
> 70 yrs old
< 2cm, node
negative,
ER +/?
636 pts.
Lumpectomy
+ tamoxifen
319 pts.
Lumpectomy
+ tamoxifen
+ XRT
317 pts.
Follow up 8.2 years
Local recurrence
– 1.3% with XRT
– 7.2% w/o XRT
No difference in
mastectomy rate,
distant metastases,
breast cancer specific
survival, or overall
survival
Hughes, et al NEJM 2004, updated
Are there indications for
radiation after mastectomy
for early stage breast
cancer?
Radiation After
Mastectomy
Retrospective review from British
Columbia
Reviewed 1,505 pts.
– T1-2N0 tumors
– Mastectomy with clear margins, no XRT
Median follow up 7 years
Performed a recursive partitioning
analysis to predict who may benefit
from XRT
Truong et al., IJROBP 2005
What are the current
techniques for
whole breast irradiation?
Treatment Position
Supine
– Arms abducted 90º or greater
– Immobilization devices
Alpha cradles, breast boards, plastic molds
Prone
–
–
–
Improve dosimetry in large, pendulous breasts
Reduction of lung volume in field
Reduction of scatter to opposite breast
Lateral decubitus
– Improve dosimetry in large, pendulous breasts
Immobilization in Supine
Position
Courtesy of L. Vallow, Mayo Clinic
Immobilization in Supine
Position
Perez et al. Principles and Practice of Radiation Oncology, 5th ed.
Prone Breast Radiotherapy
Courtesy of L. Vallow, Mayo Clinic
Clinical Target
Delineation
Radiopaque wires placed at time of
simulation to clinically outline breast
tissue
– Superior border: head of the clavicle
– Medial border: Midline
– Lateral border: 1-2cm beyond palpable
breast tissue or posterior to mid-axillary
line
– Inferior border: 1-2cm below
inframammary fold
Clinical Target
Delineation
Courtesy of L. Vallow, Mayo Clinic
Clinical Target
Delineation
Courtesy of L. Vallow, Mayo Clinic
Standard Breast
Radiotherapy
Target the entire
breast
Dose of 45-50 Gy to
whole breast
– 1.8-2 Gy per day
Electron boost to
tumor cavity
– 10-16 Gy
6 ½ weeks of
treatment
Courtesy of L. Vallow, Mayo Clinic
Tangential Breast Fields
Courtesy of L. Vallow, Mayo Clinic
Whole Breast Dosimetry
Courtesy of L. Vallow, Mayo Clinic
Whole Breast Dosimetry
Courtesy of L. Vallow,
Mayo Clinic
Alternative Fractionation
1234 women
S/p lumpectomy
XRT
50 Gy in 25 fx.
XRT
42.5 Gy in 16 fx.
Pathological node negative
Negative margin, no tumor at inked margin
Tumor < 5cm
No boost in either arm
Maximum width of breast tissue < 25cm
Whelan, et al. J Natl Cancer Inst 2002
Alternative Fractionation
Median follow up 12 years
Results at 10 yrs
50 Gy/25 fx
42.5Gy/16fx
Local Recurrence
6.7%
6.2%
Good/Excellent
Cosmesis
71%
70%
Late Skin Morbidity
3%
6%
Late Subcutaneous
Tissue Morbidity
4%
8%
Whelan, et al. ASTRO 2008
Boost to Tumor Cavity
Lyons Trial
– Randomized 1,024 patients to boost of
10Gy to tumor bed vs. no boost after 50Gy
to whole breast
– Included invasive T1-2, N0-1 tumors
– < 3cm, negative margins
– Median follow up 3.3 years
– Local recurrence at 5 years 3.6% vs. 4.5%
in favor of boost
– Disease free survival at 5 years 82% vs.
86% in favor of boost
Romestaing, et al. JCO 1997
Boost to Tumor Cavity
EORTC 22881
– Randomized 5,318 patients to boost
of 16Gy to tumor bed vs. no boost
after 50Gy to whole breast
– Included invasive T1-2, N0-1 tumors
– Negative margins
– Median follow up 10.8 years
– Local recurrence at 10 years 10.2%
vs. 6.2% in favor of boost
Bartelink, et al. JCO 2007
Dose Inhomogeneity
Wedges are traditionally used to maintain dose variance
<5-10% throughout breast
–
–
Improves dose along central axis
Significant inhomogeneity in superior/inferior portion of breast
Perez et al. Principles and Practice of Radiation Oncology, 5th ed.
IMRT for Breast
Radiotherapy
Optimize dose homogeneity
Avoid unnecessary normal tissue
radiation
Improve target volume coverage
IMRT for Breast
Radiotherapy
Courtesy of L. Vallow,
Mayo Clinic
IMRT for Breast
Radiotherapy
Review of 281 women with Stage 0-II
breast cancer treated with BCT
Static, multileaf collimator IMRT
technique
– Median planning time: 40-45 minutes
– Median # of sMLC segments: 6
– Median treatment time: <10min
– Median % of treatment with open field:
83%
Vicini, et al. IJROBP, 2002
IMRT for Breast
Radiotherapy
Outcomes
– Median volume of breast receiving % of
prescribed dose
105% prescribed dose: 11%
110% prescribed dose : 0%
115% prescribed dose : 0%
– 1% grade 3 toxicity
– 99% good or excellent cosmesis
Vicini, et al. IJROBP, 2002
IMRT for Breast
Radiotherapy
331 pts.
Early stage breast cancer
Breast IMRT
Standard XRT with
wedge compensation
All patients received lumpectomy followed by 50Gy
in 25fx
– Stratified use of boost and breast size
Significant reduction in V105, V107, V110, V115
Decrease in moist desquamation, 31% vs. 48%
Pignol, et al. JCO 2008
Forward Plan IMRT vs.
Wedges
Forward plan IMRT
Courtesy of L. Vallow, Mayo Clinic
Wedges
Forward Plan IMRT vs.
Wedges
Courtesy of L. Vallow, Mayo Clinic
What is the rationale for
partial breast
irradiation?
Partial Breast Irradiation
65-80% of breast tumor recurrences
recur around the primary site
Incidence of elsewhere failures within
the breast are equivalent in women
with or without XRT after lumpectomy
Adjuvant XRT can be completed within
5 days
Partial Breast Irradiation
Multi-catheter brachytherapy
MammoSite brachytherapy
3D-Conformal external beam radiation
therapy
Multi-Catheter
Brachytherapy
Courtesy of L. Vallow, Mayo Clinic
Multi-Catheter
Brachytherapy
Study
William
Beaumont
Ochsner Clinic
No. of Follow up 5 yr. Local
patients (months) recurrence
199
65
1.2%
160
84
2.5%
RTOG 95-17
99
44
3%
NIO, Hungary
Phase I/II
45
70
4.4%
Keisch et al., The Breast Journal 2005
Randomized Data
258 women
Stage T1N0-1mic,
Grade 1-2, negative margins
130 women
Whole breast irradiation
128 women
Partial breast irradiation
69% multi-catheter brachy
Median follow up 66 months
Local recurrence
– PBI: 4.7%
– WBI: 3.1%
Excellent/good cosmesis
– PBI: 77.6%
– WBI: 62.9%
Polgar, et al. IJROBP 2007
MammoSite
Brachytherapy
Courtesy of L. Vallow, Mayo Clinic
MammoSite
Brachytherapy
Study
No. of
patients
Median
Follow up
(months)
Local
recurrence
Good/
excellent
cosmesis
Benitez et
al.
43
65.2
0%
81.3%
Vicini et al.
1,440
30.1
1.6%
94%
Cuttino et
al.
483
24
1.2%
91%
Chao et al.
80
22.1
2.5%
88%
Haley et al.
92
24
0%
100%
Technical Aspects
Placement of catheter
– Open technique: placed at the time of surgery
Increased seroma formation
– Closed technique: placed post-lumpectomy
Decreased risk of infection
Technical requirements verified by CT
– Skin spacing > 5mm
– Balloon-cavity conformance, > 90%
– Asymmetry
MammoSite explantation rate ~ 10-20%
Inadequate Skin Spacing
• Improved
cosmetic
outcome with
>7mm skin
spacing
Courtesy of L. Vallow, Mayo Clinic
Inadequate Cavity
Conformity
Courtesy of L. Vallow, Mayo Clinic
Balloon Asymmetry
Courtesy of L. Vallow, Mayo Clinic
Complications
Study
Median Seromas
Follow up
(months)
Fat
Necrosis
Acute
dermatitis
Infection
Benitez et
al.
65.2
32.6%
10%
NR
9.3%
Vicini et al.
30.1
23.9%
1.5%
NR
8.1%
Cuttino et
al.
24
NR
NR
12%
9%
Chao et al.
22.1
45%
8.8%
NR
11.3%
Haley et al.
24
57%
10%
10%
12%
Infection and adjuvant chemotherapy can result in decreased cosmesis
Other Intracavitary
Applicators
Contura™
Savi™
ConturaTM
Contains 4
surrounding
channels
with 5mm
offset
Flexibility in
achieving
better
conformality
– Improve
normal
tissue
sparing
– Improve
PTV
coverage
ConturaTM
Vacuum port allows for improved conformity
SaviTM
SaviTM – Strut Adjusted
Volume Implant
6-10 peripheral struts
surrounding a central
strut
–
–
–
Differentially loaded
Maximize coverage
Reduce dose to normal
structures
SaviTM
Less skin spacing restrictions
Less size and shape of cavity
restrictions
SaviTM
3D-Conformal External
Beam Radiation Therapy
Courtesy of L. Vallow, Mayo Clinic
Dosimetric Comparison
PTV V100
Multi-catheter MammoSite
3D
brachytherapy brachytherapy conformal
EBRT
58%
76%
100%
PTV V90
68%
91%
100%
Normal
breast 50%
PD
Lung V20
26%
18%
48%
0%
0%
5%
Weed, et al. Brachytherapy 2005
Selection of Patients
American
Brachytherapy
Society
– > 50 yrs
– Unifocal, invasive
ductal carcinoma
– < 3cm
– Negative margins
– Node negative
American Society of
Breast Surgeons
– > 45 yrs
– Invasive ductal
carcinoma or DCIS
– < 3cm
– Negative margins
– Node negative
Less strict guidelines currently used for NSABP B39
Selection of Patients
Breast size
Lumpectomy cavity site
– Medial, parasternal
– Inframammary fold
– Retroareolar
Implants
NSABP B39/ RTOG 0413
Phase III randomized trial of whole breast
irradiation vs. partial breast irradiation
Stage 0-II Breast Cancer
S/p lumpectomy
< 3 cm, < 3 LN+
Negative margins
Whole breast irradiation
45-50 Gy/25 fx
+/- boost of 10-16 Gy
Partial breast irradiation
34 Gy/10fx BID MammoSite or
Multi-catheter brachytherapy
38.5 Gy/10fx BID 3D EBRT
Conclusions
Early stage breast cancer can be treated
with lumpectomy and radiation therapy in
the majority of patients with good outcomes
and cosmesis
Technical advances in radiotherapy
planning may allow the benefit of radiation
with less morbidity
Outcomes with long term follow-up from
NSABP B39 will further clarify the role of
PBI
Questions?