Current Status of Accelerated

Partial Breast Irradiation

Julia White MD Professor, Radiation Oncology

I have no disclosures relative to

the presented material

Agenda

• ABPI Timeline

• APBI by Method

• Clinical Trials

• Consensus Guideline

• Summary

Accelerated Partial Breast

Irradiation (APBI): Definition

Delivery of larger doses/fraction of radiation therapy (RT) to the lumpectomy cavity (plus 1-2 cm margin) after breast conserving surgery using brachytherapy or external beam irradiation techniques

Complete RT in < 5-8 days after lumpectomy instead of 6-7 weeks

17 years of APBI: What have we learned?

1997 -2000 RTOG 9517 Multi catheter APBI Phase II/ feasibility

2000-2001 Mammosite APBI Phase II/ feasibility

2002 MammoSite FDA Approval

2002-2004 ASBS Registry MammoSite APBI

2003-2004 RTOG 0319 3DCRT APBI Phase II/ feasibility

2004 NASBP B39/ RTOG 0413 Phase III opens

2006 OCOG 3DCRT RAPID Phase III opens

2009 ASTRO Consensus Guidelines

2011 OCOG 3DCRT RAPID Phase III closes

2013 NSABP B39/ RTOG 0413 Phase III closes

Lumpectomy

Breast

Advantages: Irregularly shaped

cavities, skin and chestwall sparing

RTOG 95-17 phase I/II Multi-catheter APBI

- 100 patients accrued between 1997- 2000

› 10 institutions: HDR 66, LDR 33

› 34 Gy in 10 fractions, BID 5-8 days

› Median Tsz. 1.3 cm, N-1 19%, ER/PR+ 77%

– Overall satisfaction with treatment at 5 yrs: 75%

– 94.6% would choose multicatheter APBI again

Target volume: 1.5 cm breast

tissue around the cavity

#

5 year 10 year

Median follow-up: 12.1 yrs Event (%)

# at

risk (%)

# at

risk

ISOLATED in-breast recurrence 4 3.1 84 4.2 68

In field 3 2.1 85 3.1 69

Out of field 1 1.0 85 1.0 69

In-breast & Regional recurrence 2 1.0 84 2.1 68

ALL In-breast recurrences 6 4.1 86 6.2 69

ISOLATED Regional recurrence 3 3.1 84 3.1 68

ALL Regional recurrences 5 4.1 87 5.2 71

Contralateral Breast Cancer 5 3.1 88 4.2 70

RTOG 95-17: A phase I/II trial to

evaluate multi-catheter interstitial PBI

MultiCatheter PBI (HDR/ LDR): Summary

Institution

Pt.

No.

Median

age

F/U

mo.

T size

(cm)

median

N+

%

ER +

%

Tam

%

LR

%

Exc/ good

Cosmesis

%

Oschner 163 63 65 - 15 65 - 3 -

Beaumont 199 65 65 1.1 12 - 57 1.2 99

Tufts-NEMC 32 63 84 1.3 9 79 61 9 93

*VCU 44 62 42 1.2 18 - 66 0 80

Nat. In. Onc. Budapest 45 56 81 1.2 2 82 16 6.7 97

Guys Cs 137 49 58 75 2.5 46 - - 18 81

* U. WI -low -high

183 90

63 47

48 49

1.1 1.4

0 18

100 83

57 50

2.2 4.4

95

*MCW 74 68 40 1.2 1.5 88 76 1.3 82

Ger-Austrian Multicenter 274 60.5 63 1.2 0 100 91.2 2.9 90

RTOG-9517 99 62 144 1.3 19 75 - 4 -

Median

age

60.7

T size

(cm)

median

1.35

N+

13%

ER +

84%

LR

4.8%

Exc/

good

Cosmesis

89%

DOSE

50%

80%

100%

120%

140%

200%

APBI: Single Entry Brachytherapy Devices

Dose : 34 Gy, 10 fractions 3.4 Gy BID, over 5-8 days

Minimal balloon surface-skin distance –

- ideally 7 mm,

- if 5-7 mm then confirm skin dose <145%

1st Generation: Mammosite® balloon Target volume: 1 cm breast tissue

around the balloon

Advantages: Simplified approach,

improved technology access

Initial MammoSite® Multi-institutional

Phase II Study-Manufacturer

Overview: 43 patients enrolled 5/2000- 10/2001

34 Gy, 10 fractions BID @ 1 cm, 5-8 days

Results: Median follow-up 65.2 months (n=36)

- Median Age 69 years

- All T1 N0, 79% > 10 mm in size

Grade 1-2: 77%, G3 14%

- No local recurrences

- Telangiectasias 39.5%, Retraction 20.9%

- 80% good/ excellent cosmesis

- Cosmesis worse- skin spacing < 7 mm

Keisch et al, IJROBP 2: 2003, Benitez, et al. Amer. J. Surg, 2007

ASBS APBI Registry

• 2002 – 2004: 1440 patients , 97 facilities

• 95% 34Gy/10 fractions BID, 89% > 7mm skin spacing

• > 20 Publications

• Median F/U: 58 months

Invasive: (n=1249)

• median age: 66

• median T-size: 10 mm

• 97% N-0

• ER/PR: 87%

• In-breast failure: 3.9%

DCIS: (n=194)

• median age: 62.1

• median TIS size: 8 mm

• In-breast failure: 3.4%

Vicini, IJROBP 79: 2011, Shah, IJROBP

2012

APBI Single Entry Brachytherapy:

Next Generation

Contura SenoRx SAVI Ciana medical

Advantages:

• dosimetric coverage

• sparing of skin and

chestwall

Trends in the use of implantable

APBI in the U.S.

FDA approval

of MammoSite

0.4% in 2000 versus 6.8% in 2007 p < 0.001 SEER Database

Abbott, et al, Cancer 2011

Select Single Entry Brachy APBI: Summary

Institution Pt.

No.

Median

age (yr)

F/U

mo.

T size (cm)

median

N+

%

ER +

%

Local

relapse

%

Exc/ good

Cosmesis

%

Initial

Manufacturer

Multi- Institution

43 69 65 1.0 0 - 0 81

*Rush Univ. 112 64 - 88% Tis/T1 7 - 0 80

*Tufts/ VCU 28 62 19 1.1 0 100 0 86

St. Vincent

Hospital 32 62 11 97% T-1 9 94 - 86

*Kaiser-

Permanente 51 64 16 1.2 16 86 0 95

*MUSC 111 61 46 - 8 - 5 -

*Pooled multi-

institution 483 - 24 - - - 1.2 91

*ASBS Registry 1440 65.9 54 1.0 3 51 3.8 93

Median

age

64

T size

(cm)

median

1.1

N+

5%

ER +

88%

LR

1%

Exc/

good

Cosmesis

87%

sagittal

coronal Advantage: Linear accelerator delivery

RTOG 0319 Phase I/II 3DCRT APBI

– 58 patients accrued 2003-2004

– Feasibility of external beam method for APBI

– 38 Gy in 10 Fraction, BID 5-8 days

– Overall satisfaction at 3 years 86%

– 100% would choose 3DCRT APBI again

RTOG 0319

Results at 8 year median follow-up

n

5-year

estimate

7-year

estimate

Ipsilateral Breast Failure* 4 5.8% 7.7%

Contralateral Breast

Failure 0 0% 0%

Ipsilateral Nodal

Failure** 3 5.8% 5.8%

Distant Failure 4 7.7% 7.7%

* All IBFs were in T1N0, postmenopausal patients

**All INFs were in T1N0, ER+, postmenopausal patients

Rabinovitch, ASTRO 2013

3-DCRT APBI: Summary

Institution Pt.

No.

Median

age

F/U

mo.

T size

(cm)

median

N+

%

ER +

%

Local

relapse

%

% Exc./

Good

Cosmesis

Beaumont 96 62 36 - 1 - 1 90

NYU 100 67.5 60 0.9 0 100 1 94

MGH 98 60 71 0.9 0 89 5 97

British

Columbia 127 62.6 37 - 0 82 1 82

Esperanza 105 67 60 1.4 0 96 0 100

RTOG 0319 58 61 40 1.0 8 - 6 -

Median

age

64

T size

(cm)

median

1.0

N+

1.8%

ER +

90%

LR

2.2%

Exc/

good

Cosmesis

90%

NSABP B-39/RTOG 0413 Trial Phase III

Stage 0, I-II breast cancer treated by lumpectomy

Randomization

WBI • 50-50.4 Gy (1.8-2.0 Gy)

Fractions to the whole breast

followed by boost to 60 -66.6 Gy

APBI • 34 Gy in 3.4 Gy fxs bid

Mammosite® , Contura, SAVI or

Multicatheter brachytherapy

OR

• 38.5 Gy in 3.85 Gy fxs bid

3D-CRT

Targeted accrual = 4300

NSABP B39 / RTOG 0413 • March 21, 2005 – Opened for accrual

- 3000 targeted accrual

• January 1, 2007 – Accrual closed to “low-risk”

population and targeted accrual increased

• April 11, 2013 Closed for accrual– 4,216 accrued (Among patients with follow-up, mean follow-up time is

60.5 months.)

APBI - # of patients randomized: 2107

Methods: – 70.5 % (n=1474) 3-DCRT,

– 24.3% (n=512) MammoSite/other

– 5.2 % (n=109) MultiCatheter

NSABP B39 / RTOG 0413: Population

Variable: %

Age < 50 y

50-69

> 70

38.4

47.7

13.9

Race/ Ethnicity

White

Black

Hispanic

89.8

7.1

4.1

Disease Stage

DCIS

Invasive N-0

Invasive N-1

24.3

65.4

10.1

Hormonal Status

ER or PR +

ER and Pr-

81.3

18.7

Phase III Trials Comparing APBI to WBI

Closed! Accrual

PBI

Method Eligibility

NSABP B-39/

RTOG 0413

2013 4214

3-DCRT

MST

MCT

> 18 yo, Stage 0-II, < 3cm,

N-0 – N-1 (< 3 LN+)

GEC-ESTRO

2009 1300 MCT

> 40 yo, Stage 0-II, < 3 cm,

N-0 – Nmi,

Negative margins (2 mm)

RAPID

OCOG

2012 2135 3-DCRT

> 40 yo, Stage 0-II, < 3 cm,

N-0, excludes inf. lobular

(7649)

Suitable Cautionary Unsuitable

Patient Factors Age > 60 years 50-59 < 50

BRCA 1-2 no no Yes

Path Features T-size < 2 cm 2.1-3.0 cm > 3.0 cm

T stage T-1 T-0 – T-2 T 3- T4

Margins Negative ( 2 mm) Close (< 2 mm) Positive

LVSI No Limited, focal Extensive

ER Pos. Neg. -

Multicentric Unicentric Unicentric Present

Multifocal Clinically unifocal Clinically unifocal Clinically multifocal

Histo IDC ILC -

DCIS, EIC No, No Yes, Yes (< 3 cm) > 3 cm

Nodes N stage pN0 (i+ , -) - pN1, N2-3

Nodal Surgery yes yes no

ASTRO Consensus Statement for

Treatment with APBI Outside a Clinical Trial

Smith, IJROBP,4:2009

5 year Mastectomy Rate

Brachytherapy APBI versus WBI

SEER-Medicare

• 92,735 cases

• Age > 67

• 2003-2008

3.95%

2.19%

Smith, et al. JAMA, 307:2012

5 year Mastectomy Rate

by ASTRO Consensus Guideline

SEER-Medicare

n Lump APBI EBRT p

ALL 35,9457 4.2 3.0 1.4 < 0.001/0.001

Suitable 9,966 3.7 1.6 0.8 < 0.001/0.002

Cautionary 5,509 6.7 5.4 2.2 < 0.001/0.006

Unsuitable 10,119 5.0 3.6 1.6 < 0.001/0.02

Smith G, et al., IJROBP, 2:2014

No Difference in Mastectomy Rate

in “Older Suitable” SEER-Medicare

n = 7,450

Age > 70

Distribution by ASTRO

Consensus Statement Grouping

SEER: 4,172 Breast Cancer Cases

treated with Brachytherapy Husain, Brachytherapy, 2011

Outcomes after APBI

“Cautionary”

• University of Wisconsin

• 2001-2006

• Median f/u: 60 mo.s

• 322 MCT APBI

– 79 Suitable

– 136 Cautionary

– 107 Unsuitable

• Reason Cautionary

– 63% age 50-59

– 23.5% DCIS

– 12.5 % EIC

– 9.6% 2 cm- 3cm T-size

– 8.1% ER neg.

– 7.4% ILC

– 7.4 % < 2 mm margin

– 27.9% multiple factors

McHaffie, et al, IJROBP 2011

Stage I-II: IBTR by “Cautionary”

Determinant

Age: 0%

Histopath: 12.7%

p=0.018

McHaffie, et al, IJROBP 2011

MGH: 3DCRT APBI Using 32 Gy/ 8 BID

5-Year Results of a Prospective Study

• 2000-2005

• N= 98

• Stage I

• Er/Pr +: 89%

• Median F/U: 71 mo.

Pashtan, IJROBP, 2012

ASBS MammoSite® Registry

• 1225 invasive

breast cancer

• Median f/u:

60 mo.

• 5 yr LR: 3.6%

Beitsch, Ann Surg Onc 2012

Relationship of

Breast Cancer

Recurrence and

Mortality by

absolute reduction

in 10 -year risk of

Any 1st Recurrence

Bre

ast

Can

cer

Mo

rtali

ty

-

Absolu

te r

eduction (

%)

in 1

5-y

ear

risk (9

5%

CI)

Any First Recurrence Absolute reduction (%) in 10-year risk Lancet 378: 1707-16, 2011

< 10% absolute reduction

in any recurrence risk by 10

years

RCT in Hormone Responsive pN0 Breast

Cancer Evaluating RT Benefit in Addition to

Anti Endocrine Therapy Post-lumpectomy

Clinical Trial n

F/U yrs

Age > 50 y

(%)

T sz < 2 cm (%)

ER/PR+ (%)

Tam/AI (%)

Grade 1-2 (%)

In-breast

recurrence (%)

RT No RT PMH 769 5.6 100 83 80.5 100 68.3 0.6 7.7

ABCSG 8a 869 4.48 99 90 100 100 95 0.4 5.1

CALGB

9343 626 12.6 100 98 97 100 - 2 8

Low risk features: Older age, pN0, small size, ER/PR+,

G1-2, anti endocrine therapy

Recurrence rate indicates UNLIKELY survival

benefit from breast radiotherapy

OCOG RAPID Early Reporting

of Cosmetic Results

WBI

ABPI-

3DCRT

Difference

APBI-WBI

(95% CI) p value

Baseline

n=1995 17% 19% 2% (-2-5%) 0.35

3 years

n=850 19% 32% 135 (7-19%) < 0.0001

Adverse Cosmetic Outcome ( Fair –Poor)

Nurse Assessment at Baseline and 3 years

Olivotto et al, JCO 2013

APBI so far has demonstrated acceptable local control in

mostly low risk cases: Stage 1, ER+, > 60 yo breast

cancer patients

Need to complete randomized trials to define broader

applicability and durability of outcome in comparison to

standard WBI

Rigorous attention to technical delivery and Q/A is

crucial

Summary: APBI

Thank you