Indications for Post-
Mastectomy Radiotherapy and
Considerations in Treatment
Planning
Lori J. Pierce M.D., FASTRO
Professor of Radiation Oncology
University of Michigan Comprehensive Cancer Center
Post-Mastectomy Radiotherapy
Effect of RT after mastectomy and ALND on 10-year risk of locoregional
and overall recurrence and 20-year risk of BC mortality in No disease
EBCTCG, Lancet 2014
Post-Mastectomy Radiotherapy
PMRT and High-Risk Operable Breast Cancer Treated with CMF or Tamoxifen: DBCG 82b and 82c
Kaplan-Meier estimates of overall survival among women with high risk disease (all N+ and HR N-) treated with CMF + RT (82b) and Tam+ RT (82c)
Overgaard et al, NEJM 1997
Overgaard et al, Lancet 1999
Post-Mastectomy Radiotherapy
PMRT in High-Risk Breast Cancer Following CMF: 20-Year Results of British
Columbia Trial
Chemo-alone Chemo + RT
arm therapy arm
Survival, # events/ Survival, # events/
Outcome %‡ # pts. %‡ # pts. RR P
All 318 patients
Survival free of isolated 74 27/154 90 12/164 0.36 .002
locoregional disease
Systemic breast cancer- 31 104/154 48 84/164 0.66 .004
free survival
Breast cancer-specific 38 95/154 53 75/164 0.67 .008
survival
Overall survival 37 101/154 47 89/164 0.73 .03
Ragaz et al, JNCI 2005
Post-Mastectomy Radiotherapy
Effect of RT after mastectomy and axillary dissection (Mast+AD) on 10-year
risks of locoregional and overall recurrence and on 20-year risk of breast cancer
mortality in 3131 women with pathologically node-positive (pN+) disease
EBCTCG, Lancet 2014
Radiotherapy reduces the risk of
loco-regional recurrence as first recurrence
by two-thirds
For BCT: In the hypothetical absence of any other causes
of death, 1 breast cancer death would be avoided for
every 4 local recurrences avoided.
For PMRT in N+ disease:
One breast cancer death would be avoided in 20 years
after RT for every 1.5 recurrences avoided 10 years
after RT.
Post-Mastectomy Radiotherapy
Effect of radiotherapy (RT) after mastectomy and axillary dissection (Mast+AD) on 10-year risks of
locoregional and overall recurrence and on 20-year risk of breast cancer mortality in 1314 women with
one to three pathologically positive nodes (pN1-3) and in 1772 women with four or more pathologically
positive nodes (pN4+) EBCTCG, Lancet 2014
Post-Mastectomy Radiotherapy
Effect of radiotherapy (RT) after mastectomy and axillary dissection (Mast+AD)
on 10-year risks of locoregional and overall recurrence on 20-year risk of breast
cancer mortality in 1133 women with one to three pathologically nodes (pN1-3) in
trials in which systemic therapy was given to both randomized groups.
EBCTCG, Lancet 2014
1-3 Positive Nodes Following Mastectomy and
Systemic Treatment
MD Anderson
Era # pts LRR without RT* LRR with RT* Early
(1978-97) 505 9.5% 3.4%
p=.028
Later 522 2.8% 4.2%
(2000-07) p=.48
*at 5 years
McBride et al, IJROBP 2014
Post-Mastectomy Radiotherapy: Indications for Treatment
The Danish Breast Cancer Cooperative Group
• Paraffin blocks from 1,000 patients with 8 or more nodes
removed randomized on DBCG 82B and 82C stained for ER, PR
HER-2
• Median F/U 17 years for 1,000 patients
• Established three prognostic subgroups
Kyndi et al, Radio Oncol 2009
Post-Mastectomy Radiotherapy: Indications for Treatment
High local recurrence is not associated with large survival reduction after PMRT
3 prognostic groups established:
Good: four out of five favorable criteria (< 3 positive nodes,
tumor size < 2 cm, grade 1; ER + or PR+, HER2 neg)
Poor: at least two out of three unfavorable criteria (>3
positive nodes, tumor size > 5 cm, grade 3)
Intermediate: other than good or poor
Kyndi et al, Radio Oncol 2009
5-year local recurrence probability and 15-year breast cancer mortality within
the good, the intermediate and the poor prognostic subgroups in high-risk
breast cancer patients randomly assigned to receive or not receive PMRT
Kyndi et al, Radio Oncol 2009
Post-Mastectomy Radiotherapy
SUPREMO TRIAL
(Selective Use of Postoperative Radiotherapy aftEr
MastectOmy)
under auspices of Scottish Cancer Trials Breast Group
Phase III trial of PMRT in intermediate risk breast cancer
• pT1N1 or pT2 N0-1
• negative mastectomy margins
• 1-3 positive nodes or N0 with grade 3 histology or ALI
Rec+/HER- Rec+/HER+ Rec-/HER- Rec-/HER+
Kaplan-Meier probability plots of overall survival and locoregional recurrence probabilities in
high-risk breast cancer patients as a function of randomization to postmastectomy radiotherapy.
Kyndi et al, JCO 2008
Percentage of patients with locoregional recurrence at 10 years according to
various subgroups in the B-14/B-20 trials (node neg, ER+, Tam, chemo)
Mamounas et al, JCO 2010
21 Gene Recurrence Score and Locoregional Recurrence
Recurrence Score and Locoregional Recurrence
Ten-year Kaplan-Meier estimates of the proportions of locoregional recurrence according to
recurrence score , initial locoregional treatment, and age in the B-14/B-20 trials.
Mamounas et al, JCO 2010
Recurrence Score and Locoregional Recurrence
Multivariate Cox Regression Analysis of Predictors of Locoregional Recurrence in the
Cohort of 895 Tamoxifen-Treated Patients from NSABP Trials B-14 and B-20
Hazard Wald
Variable Ratio 95% CI Test P
Age (> 50 v < 50) 0.40 0.25 to 0.65 .0002
Mastectomy v L + XRT 0.62 0.39 to 0.99 .047
Clinical tumor size (> 2 v < 2 cm) 0.98 0.61 to 1.59 .933
Tumor grade (moderate v well) 1.10 0.54 to 1.92 .113
Tumor grade (poor v well) 1.76 0.89 to 3.48
Recurrence score 2.16 1.26 to 3.68 .005
Hypothesis-generating; needs validation
Mamounas et al, JCO 2010
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Post-Mastectomy Radiotherapy
PMRT
NIH Consensus Conference
Consensus Statements (ASTRO, ACR, ASCO)
For which patients should PMRT be recommended?
4 positive axillary nodes
T4 lesions
tumor invading skin, musculature
positive margins
Controversial with T3; high risk node negative disease; and 1-3
positive nodes. These patients should be seen in consult by a
Radiation Oncologist.
Are the risk factors for LRR after neo-adjuvant
chemotherapy the same as after adjuvant
chemotherapy?
Post-Mastectomy Radiotherapy
Patterns of LRF in Patients Receiving Neoadjuvant
Chemotherapy
Combined Analysis of B-18 & B-27
• Analysis of 2 prospective trials to assess rates of LRF after BCT and
mastectomy
• No regional RT in BCT patients; no PMRT
• Path CR = no invasive disease in breast + negative axillary nodes
• Median F/U 12.1 yrs.
Mamounas et al, JCO 2012
Radiation Questions after Preoperative Systemic Therapy
CONSORT diagram for NSABP B-18 & B27 trials
Mamounas et al, JCO 2012
Radiation Questions after Preoperative Systemic Therapy
NSABP B-18 & B27
Predictors of LRR after NAC: Combined Analysis
• BCT: RT to breast only; no regional RT
• No PMRT allowed per NSABP policy
Mamounas et al, JCO 2012
10-Year Cum. Incidence of LRR According to Treatment Arm
14.3
12.2
8.5 9.5
Mamounas et al, JCO 2012
P=0.05
P=0.02
P=0.08
Radiation Questions after Preoperative Systemic Therapy
LRR at 10 yrs with BCT in
(A) age > 50 yrs
(B) age < 50 yrs
LRR at 10 yrs with mastectomy on
(A) < 5 cm
(B) > 5cm
Mamounas et al, JCO 2012
Observations from NSABP trials:
BCT • Increased rates of LRR with residual disease in the
breast and/or lymph nodes
• Increased rates of LRR in younger women
Mastectomy • Increased rates of LRR with residual disease in the
breast and/or lymph nodes
• Increased rates of LRR for cancers > 5 cm
• Low rates of LRR with path CR in breast and nodes
Breast Cancer Symposium Abstract 61: Loco-regional Recurrence (LRR) After Neoadjuvant Chemotherapy (NAC): Pooled-analysis
Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC)
Eleftherios P. Mamounas, Patricia Cortazar, Lijun Zhang, Gunter Von Minckwitz,
Keyur Mehta, David A. Cameron, Herve R. Bonnefoi, Luca Gianni,
Pinuccia Valagussa, Norman Wolmark, Sibylle Loibl, Jan Bogaerts,
Sandra M. Swain, Rajeshwari Sridhara, Joseph P. Costantino,
Stewart J. Anderson, Priya Rastogi, Charles E. Geyer Jr., Holger Eidtmann,
Bernd Gerber and Michael Untch
National Surgical Adjuvant Breast and Bowel Project and the UF Health Cancer Center - Orlando Health, Orlando, FL; U.S.
Food and Drug Administration, Silver Spring, MD; German Breast Group/University Frankfurt, Neu-Isenburg, Germany;
German Breast Group, Neu-Isenburg, Germany; University of Edinburgh, Edinburgh, United Kingdom; Institut Bergonie Cancer
Center, Bordeaux, France; San Raffaele Scientific Institute, Milan, Italy; Fondazione Michelangelo, Milan, Italy; National
Surgical Adjuvant Breast and Bowel Project; The Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA;
German Breast Group/Sana Klinikum Offenbach, Neu-Isenburg, Germany; European Organisation for Research and
Treatment of Cancer, Brussels, Belgium; MedStar Washington Hospital Center, Washington, DC; Biostatistical Center,
National Surgical Adjuvant Breast and Bowel Project and Department of Biostatistics, University of Pittsburgh Graduate School
of Public Health, Pittsburgh, PA; University of Pittsburgh Medical Center, Pittsburgh, PA; Massey Cancer Center, Virginia
Commonwealth University School of Medicine & NRG Oncology, Richmond, VA; University Kiel, Kiel, Germany; University
Rostock, Rostock, Germany; Helios Klinikum Berlin-Buch, Berlin, Germany
5-Year Cumulative Incidence of LRR:
By Breast pCR and Path Nodal Status
3.3
8.2
13.1
(n=300)
(n=553)
(n=1188)
0
5
10
15
20
25
ypT0/is ypN0 ypT1-3 ypN0 ypTany ypN+
5-Y
ear C
um
ula
tive I
ncid
en
ce o
f L
RR
(%)
3.3
8.2
13.1
ypT0/is
ypN0
ypT1-3
ypN0
ypTany
ypN+
5-Y
ear
Cu
mu
lati
ve In
cid
en
ce o
f L
RR
(%
)
25
20
15
10
5
0 7.2
5.9
10.3(n=887)
(n=1274)
(n=1050)
0
5
10
15
20
25
ypT0/is ypN0 ypT1-3 ypN0 ypTany ypN+
5-Y
ear C
um
ula
tive I
ncid
en
ce o
f L
RR
(%)
7.2
5.9
10.3
7.2
5.9
10.3
ypT0/is
ypN0
ypT1-3
ypN0
ypTany
ypN+
Mastectomy Lumpectomy
Mamounas et al, BCS 2014
25
20
15
10
5
0
5-Year Cumulative Incidence of LRR According to
Tumor Subtypes
4.2
9.2
14.8
9.7
12.2
(n=1894)
(n=596)
(n=709)
(n=965)
(n=1088)
0
5
10
15
20
25
HR+/
HER2-,
Gra
de 1/2
HR+/
HER2-,
Gra
de 3
HR-/H
ER2+
HR+/
HER2+
HR-/H
ER2-
5-Y
ear
Cu
mu
lati
ve I
ncid
en
ce o
f L
RR
(%)
4.2
9.2
14.8
9.7
12.2
HR+/HER2-
GR 1,2 HR+/HER2-
GR 3
HR-/HER2+ HR+/HER2+ HR-/HER2-
5-Y
ear
Cu
mu
lati
ve In
cid
en
ce o
f L
RR
(%
) 25
20
15
10
5
0
Mamounas et al, BCS 2014
• Data in all pN+ mastectomy patients suggest rates of LRF which
justify strong consideration of PMRT particularly if cN+ and also
pN+
• RT not randomized so uncertain what impact RT would have had
on survival
• RT not randomized so uncertain whether a patient with positive
node negative nodes would have the same survival +/- RT
Use of neo-adjuvant therapy requires a
multi-disciplinary team.
Radiation Treatment Planning
for Breast Cancer:
Indications and Treatment
Planning Techniques
XYZ03 34
Patterns of Failure
• Help define regions to be treated
• Depending upon situation, target regions can include:
– Breast (especially lumpectomy cavity)
– Chest wall (especially mastectomy scar)
– Axillary lymph nodes
– Supraclavicular lymph nodes
– Internal mammary lymph nodes
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RT Treatment Planning
BCS vs. BCS + RT in Early Stage Breast Cancer
No. of % Local Recurrence F/U
Trial Patients No RT RT (yr)
NSABP B-06 1262 39 14 20
Milan III 579 24 6 10
Ont 837 35 11 8
Swedish 381 24 9 10
British 418 35 13 6
Scottish 589 25 6 5
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RT Treatment Planning
Loco-Regional Recurrence Patterns after Mastectomy and
Doxorubicin-Based Chemotherapy
Sites of LRR
Site of LRR Isolated LRR (%) Total LRR (%)
Chest Wall 98 68
Supraclavicular 33 40
Axilla 17 14
Infraclavicular 8 7
Internal mammary --- 8
Katz et al, J Clin Oncol 2000
LRR first
Breast cancer mortality
EBCTCG ,
Lancet 2014
Ax sampling
+/- RT
Ax sampling
+/- RT
ALND +/- RT
ALND +/- RT
Frequency and Localization of Locoregional Recurrence (first site of
failure) as a Function of Radiation Therapy
Localization of Recurrence
No Local Chest Sup./Inf. All
Treatment Recurrence Wall Axilla Clavicular Recurrences
Radiotherapy 92% 5% (2%) 2% (1%) 2% (1%) 8% (3%)
No radiotherapy 67% 16% (3%) 13% (2%) 5% (2%) 33% (6%)
Data from 3,083 patients included in DBCG 82 b & c trials
Numbers in parentheses indicate patients with concomitant distant metastasis
Overgaard et al, Sem Rad Onc 1999
Patterns of Failure in Danish Trials 82b and 82c
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RT Treatment Planning
Risk of Histologic Internal Mammary Chain Involvement According
to Histologic Axillary Node Status and Tumor Site
No. of IMC
Axillary Status Tumor site Patients Involvement (%)
N (–) External 332 8
Internal or central 299 11
N (+) External 464 22
Internal or central 331 37
Data on 1,426 patients included in an IMC dissection trial: Adapted from
Lacour et al.
RT Treatment Planning
Results of Randomized Trials Comparing IMN Prophylaxis to
Observation
Disease-free Survival Overall Survival F/U
Author No. patients Rx Obs Rx Obs Yrs.
Hennequin 1,334 NS NS 62 59 10
Morimoto 192 83 87 92 93 5
Meier 123 --- --- 74 60 10
central/medial tumors 86 60 (.03) ---
Fisher (B04) 717 57 55 59 54 10
Host, 186 57 43 (.04) 58 53 (.15) 10
(Oslo II, Stage II)
Lacour, 1,453 56 51 56 53 10
Inst. Gustave Roussy N+ central/medial tumors 53 28 (.05) 15
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RT Treatment Planning
BCT
T1-T3 N(+)
-or-
N(-) with primary tumor 5 cm
-or-
primary tumor 2 cm
and <10 axillary nodes removed
and ER-, SBR grade 3, -or-
lymphovascular invasion
Standard Breast RT
RT to Breast + IMN + SCV
Axilla
National Cancer Institute of Canada
MA.20 Phase III Trial
Regional Radiation Therapy in Early Stage Breast Cancer
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Clinical Implications of the MA 20 Trial
MA 20
5-Year Results
WBI WBI + RNI p
Isolated LR DFS* 94.5% 96.8% .02
Distant DFS 87.0% 92.4% .002
DFS 84.0% 89.7% .003
OS 90.7% 92.3% .07
*identical no. IBTR’s in each group
Whelan et al, ASCO 2011
XYZ03 43
Clinical Implications of the MA 20 Trial
MA20
Adverse Events
WBI WBI + RNI p
Pneumonitis 0.2% 1.3% .01
> grade 2
Lymphedema 4.1% 7.3% .004
F/P cosmesis 29% 36% .047
Whelan et al, ASCO 2011
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RT Treatment Planning
EORTC Phase III Trial 22922/10925
Internal Mammary and Medial Supraclavicular Irradiation in
Stages I-III Breast Cancer
No RT to IM-MS
nodes
RT to IM-MS nodes
to 50 Gy
N ()
-or-
N (-)
with medial/
central lesions
Inclusion criteria: Tx, T0-T3, N0-N2
Mastectomy or BCT
EORTC 22922/10925
• Accrual 7/96 – 1/04
• 4004 patients randomized
• 10.9 years median F/U
• ~75% BCT
No IMN-MS IM-MS
Endpoint (n=2002) (n=2002)
Local recurrence 5.3% 5.6%
Regional recurrence 4.2% 2.7%
Distant recurrence 19.6% 15.9%
DFS 69.1% 72.1% p=0.44
Deaths from B.C. 310 259
Metastases-free survival 75.0% 78.0% p=.02
Overall survival 80.7% 82.3% p=.056
European Cancer Congress 2013
These results should be considered when
discussing the relative merits of PMRT in
patients with 1-3 positive nodes.
XYZ03 47
Radiation Therapy
• Uses high energy ionizing x-ray beams (MV)
• Photons interact with electrons resulting in direct and
indirect effects
• Ultimately leads to reproductive cell death or
apoptosis
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Direct and Indirect Action
NEGATIVE
ION
photon
photon
OH
INDIRECT ACTION
DIRECT ACTION
20Å
e
p
e
p
H20
XYZ03 49
Therapeutic Ratio
• Tumor and normal tissues sustain damage after each
radiation treatment
• Normal tissues better able to repair damage up to a
point
• Ideally want sufficient dose to eradicate residual
disease with acceptable normal tissue toxicity
XYZ03 50
Adjacent Normal Tissues & Associated Complications
• Involved breast (poor cosmetic outcome)
• Uninvolved breast (contralateral breast cancer)
• Chest wall (rib fracture, sarcoma)
• Lungs (pneumonitis, lung cancer)
• Lymphatics (lymphedema)
• Brachial plexus (transient weakness)
• Heart (primarily CAD)
Magnitude of Cardiac Risk with RT
No threshold Dose effect on
the heart
Darby et al, NEJM 2013
Magnitude of Cardiac Risk with RT
Cumulative risks for 50-year old after breast cancer diagnosis
Darby et al, NEJM 2013
10 Gy
3 Gy
Avoidance of Cardiac Toxicity
Risk of Cardiac Death after Adjuvant Radiotherapy for Breast Cancer
M.D. Anderson (SEER data)
Kaplan-Meier survival curves by breast cancer laterality and year of diagnosis.
blue lines = 1973-1979 cohort solid lines = left
red lines = 1980-1984 cohort dotted lines = right
green lines = 1985-1989 cohort Giordano et al, JNCI 2005
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RT Treatment Planning
XYZ03 55
3-D Conformal Treatment Planning
• CT based
• Explicit definition of target and normal tissue
structures
• Optimization of radiation dose distribution
• Homogenous dose to target while minimizing
the dose to surrounding normal structures
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RT Treatment Planning
CT-Based Treatment Planning
Superior Tangents Inferior Tangents with Block
Cardiac Effects of Modern Radiotherapy
Individualizing Treatment Planning Techniques
Box plots of CW
and heart V30 and
NTCP by technique
Pierce et al, IJROBP 2002
XYZ03 58
RT Treatment Planning
Definition of Supraclavicular and Infraclavicular Nodes
Transverse CT sections of SCV and IFV fossae
Madu, …Pierce, Radiology 2001
XYZ03 59
Supraclavicular and infraclavicular nodes
Madu, …Pierce, Radiology 2001, edited
Potential benefits:
1) Decreased shoulder
stiffness and pain
2) Decreased arm
lymphedema
XYZ03 60
RT Treatment Planning
95% IDL
XYZ03 61
RT Treatment Planning
IMRT =
Intensity Modulated Radiation Therapy
• 3D conformal therapy which allows the photon fluence/intensity
pattern to vary across a field.
Instead of one uniform intensity across a field, the intensity can
vary to achieve a more conformal plan
60-69
55-59
53-54
48-52
45-47
40-44
30-39
20-29
10-19
5 - 9
1 - 4
2 – D Tangents
IMRT Tangents
60-69
55-59
53-54
48-52
45-47
40-44
30-39
20-29
10-19
5 - 9
1 - 4
med lat
Randomized Studies of Outcomes Using 2-D vs.
IMRT Planning in Early Stage Breast Cancer
Institute # patients Results
Sunnybrook, 331 Significant reduction in moist desquamation;
Vancouver Island, BC IMRT use did not correlate with pain and QOL
Pignol et al, JCO 2008
Royal Marsden, UK 306 Significant reduction in skin induration at pectoral and
inframammary folds, boost site at 2 and 5 years;
No difference in pain or QOL
Donovan et al, Radio & Onc 2007
Cambridge, UK 667 Significant reduction in telangiectasia and signif
improvement in cosmesis with IMRT
Patient-reported outcomes at 5 yrs not sign diff
Mukesh et al. JCO 2013
Mukesh et al. Radioth Oncol 2014
XYZ03 66
RT Treatment Planning
• Treatment planning techniques have resulted in decreased rates of cardiac mortality over the years.
• Standard 2D techniques used to treat the intact breast only result in excellent rates of tumor control.
• CT-based planning may reduce the exposure of the heart to radiotherapy for left-sided breast cancers and can reduce the volume of lung treated in some cases.
• IMRT techniques improve dose homogeneity and have been shown to reduce skin toxicity and improved cosmesis in some women compared to 2D techniques.
• No one planning technique is uniquely superior for all cases. Individualized treatment planning is critical to minimize radiation-associated long-term toxicities.
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