Post-Mastectomy Radiotherapy: Indications for...

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

XYZ03 19

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

XYZ03 35

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

XYZ03 36

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

XYZ03 39

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

XYZ03 41

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

XYZ03 42

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

XYZ03 44

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

XYZ03 48

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

XYZ03 54

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

XYZ03 56

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.