BREAST CONSERVATION TREATMENT IN EARLY STAGE...

BREAST CONSERVATION TREATMENT

IN EARLY STAGE DISEASE AND DCIS

LAWRENCE J. SOLIN, MD, FACR, FASTRO

Chairman

Department of Radiation Oncology

Albert Einstein Healthcare Network

Philadelphia, PA

Professor (Adjunct)

Temple University

Philadelphia, PA

Professor Emeritus

University of Pennsylvania

Philadelphia, PA

Radical mastectomy

Breast conservation

treatment with radiation

COMPONENTS OF BREAST

CONSERVATION TREATMENT (BCT)

1. Excise the primary tumor

2. Stage the axilla (invasive cancer)

3. Radiation treatment (whole breast)

4. Systemic therapy as indicated

ELIGIBILITY FOR BCT

Stage: DCIS or clinical T1-2, N0-1

Unicentric disease

- Clinical examination

- Radiologic imaging

Able to excise primary tumor

- Negative margins preferred

Satisfactory cosmetic outcome

Absence of contraindications to BCT

CONTRAINDICATIONS TO BCT

Absolute

Diffuse microcalcifications

Gross multicentric disease (GMD)

Diffusely positive margins of resection

Collagen vascular disease

- e.g., SLE, scleroderma

- Excluding rheumatoid arthritis

Pregnancy (except late pregnancy?)

Previous radiation to the breast (?)

Relative (cosmetic contraindications)

Large tumor-to-breast ratio (neoadjuvant chemo?)

Subareolar location of tumor (?)

RANDOMIZED TRIALS OF RADIATION AFTER

BREAST CONSERVATION SURGERY

No. of Length reported No. of randomized of follow-up Study trials patients (years) locations Whole Breast Fractionation Standard Many >10,000 >20 Worldwide BCS/RT vs. mastectomy BCS +/- RT Accelerated Accelerated partial breast irradiation (APBI)

Fisher C, JCO, 2014

RADIATION FRACTIONATION SCHEMAS

LONG TERM OUTCOMES AT 20 YEARS OR MORE

AFTER STANDARD (WHOLE BREAST) RADIATION

Endpoints Outcome - Local control High - Survival High - Cosmesis High - Complications Low

Standard RT remains the “gold standard” and

sets the bar very high for other RT techniques

DIRECT RELATIONSHIP OF LOCAL CONTROL TO SURVIVAL: OVERVIEW

DATA FOR RANDOMIZED TRIALS OF RADIATION AFTER LUMPECTOMY

FOR INVASIVE PRIMARY BREAST CARCINOMA

Modeling of data:

4 Local recurrences directly lead to

1 avoidable breast cancer death with

standard whole breast radiation

10-y gain 21.7%

Overview, Lancet, 2005

Updated data:

Local recurrence – 25.1% no RT

7.1% with RT

4:1 ratio confirmed

Overview, Lancet, 2011

DIRECT RELATIONSHIP OF LOCAL CONTROL TO SURVIVAL: OVERVIEW

DATA FOR RANDOMIZED TRIALS OF RADIATION AFTER LUMPECTOMY

FOR INVASIVE PRIMARY BREAST CARCINOMA

Overview, Lancet, 2011 4:1 Ratio confirmed

STANDARD WHOLE BREAST RADIATION TREATMENT

Standard

dose

distribution

Segmented IMRT

Vicini, 2006

BREAST IMRT (INTENSITY MODULATED RT)

PROGNOSTIC FACTORS FOR LOCAL CONTROL AFTER BREAST

CONSERVATION TREATMENT WITH RADIATION

Significant factors for local control Lower risk Higher risk Pathology margins of Negative Positive tumor excision or close Patient age Older Younger Radiation boost dose to Boost No boost the primary tumor site (Higher dose) (Lower dose) Adjuvant systemic therapy Yes No Hormone receptor Positive Negative status Emerging biologic Lower Higher factors risk risk

SSO-ASTRO CONSENSUS GUIDELINE ON MARGINS

Moran, JCO, IJROBP, Ann Surg Oncol, 2014

“The use of no ink on tumor as the standard for an

adequate margin ….. is associated with low rates of

IBTR and has the potential to decrease re-excision

rates, improve cosmetic outcomes, and decrease

health care costs.”

0

0.05

0.1

0.15

0.2

0.25

1 mm 2 mm 5 mm

Positive

Close

Negative

Houssami, EJC, 2010

MINIMUM NEGATIVE MARGIN WIDTH

LO

CA

L R

EC

UR

RE

NC

E (

%)

25

20

15

10

5

10-YEAR PREDICTED LOCAL RECURRENCE ACCORDING TO MARGIN STATUS AND MINIMUM NEGATIVE MARGIN WIDTH: META-ANALYSIS

16%

12%

7%

12%

10%

6%

9%

7%

4%

0

P = .097 Adjusted test for trend

P > .2 Adjusted for endocrine

therapy or radiation boost

Houssami, Ann Surg Oncol, 2014

1.47

1.0

(reference) 0.95

0.65

OD

DS

RA

TIO

P = 0.12

P = 0.21 (test for trend)

MINIMUM NEGATIVE MARGIN WIDTH

META-ANALYSIS FOR LOCAL RECURRENCE

ACCORDING TO MARGIN WIDTH

Positive vs negative

Odds Ratio = 2.44

P < .001

Close vs negative

Odds Ratio = 1.74

P < .001

>0 mm vs 5 mm

P = .021

Bartelink, JCO, 2007

EORTC RANDOMIZED TRIAL OF A BOOST AFTER 50 GY

WHOLE BREAST RADIATION IN 5,318 PATIENTS

Bartelink, JCO, 2007

Age

groups

Interaction

of age

with boost

EORTC RANDOMIZED TRIAL OF A BOOST AFTER 50 GY

WHOLE BREAST RADIATION IN 5,318 PATIENTS

Nguyen, JCO, 2008

LOCAL FAILURE ACCORDING TO BIOLOGIC FACTORS AFTER BREAST CONSERVATION TREATMENT WITH RADIATION

Solin, Clinical Breast Cancer, 2009 Yang, Breast Cancer Res Treat, 2008

Haffty, IJROBP, 2008

p = .047

ER/PR

Neg

Pos (Hormones)

Neg

Pos (Hormones)

Lo

ca

l R

eg

ion

al F

ail

ure

at

10

Ye

ars

(%

)

40

30

20

10

Age < 50

P = .057

Age ≥ 50

P = .66

Recurrence Score

0

LOCAL-REGIONAL FAILURE ACCORDING TO 21-GENE RECURRENCE

SCORE ASSAY AFTER BREAST CONSERVATION TREATMENT

Mamounas, JCO, 2010 Solin, BCRT, 2012

NSABP B14 AND B20 Age < 50

P = .09

Age ≥ 50

P = .57

ECOG E2197

LRR in Patients with Lumpectomy + Breast XRT in NSABP B-28

0 2 4 6 8 10

0.0

0

.1

0.2

0

.3

0.4

0

.5

Time in Years

Cu

mu

lati

ve I

ncid

en

ce R

ate

RS Low RS Intermediate RS High

P-value = 0.12

10.5%

6.2%

3.9%

N LRR Events

131 6

117 7

88 10

0 2 4 6 8 10

0.0

0

.1

0.2

0

.3

0.4

0

.5

Time in Years

RS Low RS Intermediate RS High

P-value = 0.044

N LRR Events

43 0

49 7

33 4

12.8%

14.3%

0.0%

1-3 Positive Nodes

(N=336) >4 Positive Nodes

(N=125)

META-ANALYSIS OF LOCAL FAILURE ACCORDING

TO THE USE OF BREAST MRI STUDY

DCIS or Invasive Breast Carcinoma

No. Subset pts P value DCIS 136 .58 Invasive CA 620 .62

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8CO

NT

RA

LA

TE

RA

L B

RE

AS

T C

AN

CE

R (

%)

YEARS

Breast MRI

No breast MRI

P = .39

6%6%

Solin, JCO, 2008

No difference: BCT vs mastectomy Use of RT All P > .2 Houssami, JCO, 2014

POTENTIAL ADVERSE CONSEQUENCES OF BREAST MRI

Breast MRI Odds Yes No ratio P value Delay to surgery Bleicher, 2009 22.4 days .011 Hulvat, 2010 43 days 32 days .054 Landercasper, 2010 14 days 8 days .001 Krishnan, 2008 41 days 27 days < .001 Increased use of (ipsilateral) mastectomy Houssami, 2008 8% (1%)* Turnbull, COMICE, 2010 7% (2%)* 1% Pengel, 2009 9% 0% Katipamula, 2009 54% 36% 1.7 <.0001 Bleicher, 2009 28% 20% 1.8 .024 Sorbero, 2009 1.43 .005 Hulvat, 2010 1.8 .33 Increased use of contralateral prophylactic mastectomy Sorbero, 2009 9.2% 4.7% 2.04 .001 *Pathologically avoidable

IS THERE A GROUP OF PATIENTS

FOR WHOM RADIATION CAN BE OMITTED?

NSABP B-21

Fisher, JCO 2002

EVALUATION OF RADIATION BENEFIT IN FAVORABLE SUBSETS OF

PATIENTS: RANDOMIZED TRIALS OR SEER DATA

Fyles, EBCC, 2010

T1-2, N0 Age > 50 years

8.5% better at 10 years

T1 N0, Age > 70 years, ER positive

4.6% better at 10 years

Hughes, JCO, 2013

8% better at 10 years

T1, Age > 70 years, ER positive

SEER, Smith B, JNCI, 2006

T1 N0, Age > 70 years, ER positive

Kunkler, SABCS, 2013

3% better at 5 years

p = .001

T1-2 (up to 3cm)

Age > 65 years,

ER positive

Consider

comorbidity,

life expectancy

Underpowered

for survival,

other endpoints

•Local - Lumpectomy plus radiation - Lumpectomy alone - Mastectomy

•Systemic - Tamoxifen

•Optimal treatment strategy is unknown!

DCIS: MANAGEMENT OPTIONS

RATIONALE FOR RADIATION TREATMENT

AFTER LUMPECTOMY FOR DCIS

• All five randomized trials show that radiation reduces the rate of local recurrence after lumpectomy, generally by about half

• Retrospective, institutional studies of lumpectomy alone are hypothesis generating, not hypothesis testing

• “[P]atients who may avoid radiation therapy have not been reproducibly and reliably identified by any clinical trials.” (1999 DCIS Consensus Conference Statement, Cancer, 2000)

Oxford Overview of Randomized Trials of BCS±RT for DCIS

Study Entry Women random-

ised

Median follow-

up

Surgery* Negative margins required

%

with boost

Data available:

NSABP B-17 1985-90 818 16.5 y WLE (37% ad) Yes

9%

EORTC 10853 1986-96 1010 10.4 y WLE (20% ad) Yes

5%

Swedish BCCG 1987-99 1067 8.4 y Sect res (17% ad) No

2%

UK/ANZ DCIS† 1990-98 1037 4.8 y WLE (No ad) Yes NR‡

Data unavailable:§

RTOG 9804 1999-06 636 N/A WLE (No ad) Yes NR‡

* WLE: wide local excision; ad: axillary dissection; Sect res: sector resection † 2x2 factorial design: ±RT±Tam ‡

Boost not recommended § Some patients still taking tamoxifen

Median follow-up for all trials with data available: 8.9 y

Darby, JNCI Monograph, 2010

5-year gain 5.4 % (SE 0.8)10-year gain 8.5 % (SE 1.3)

logrank 2p < 0.001

BCS+RT 6.8%

8.5

3.1

BCS15.4%

3723 women

17:42:03 9 Sep 2009Provisional results: subject to revision

(Name: gr_cis_sc_rt_rlilii_all_0)

0

10

20

30

40

50

60

Ips. B

RE

AS

T R

EC

UR

RE

NC

E (

Inv o

nly

) (%

)

0 5 10 15Years since randomisation

DCIS: BCS + RT vs. BCSIps. BREAST RECURRENCE (Inv only)

5-year gain 10.5 % (SE 1.2)10-year gain 15.2 % (SE 1.6)

logrank 2p < 0.001

BCS+RT12.9%

18.1

7.6

BCS28.1%

3723 women


(Name: gr_cis_sc_rt_rlili_all_0)

0

10

20

30

40

50

60

Ips. B

RE

AS

T R

EC

UR

RE

NC

E (

CIS

& In

v)

(%)


DCIS: BCS + RT vs. BCSIps. BREAST RECURRENCE (CIS & Inv)

Oxford Overview of Randomized Trials of BCS±RT for DCIS


5-year loss 0.4 % (SE 0.4)10-year loss 0.5 % (SE 0.8)

logrank 2p > 0.1; NS

BCS+RT 4.1%

1.0

1.4

BCS 3.7%

3726 women


(Name: gr_cis_sc_rt_bcdth_all_0)

0

10

20

30

40

50

60

BR

EA

ST

CA

NC

ER

MO

RT

ALIT

Y (

%)


DCIS: BCS + RT vs. BCSBREAST CANCER MORTALITY

EBCTCG Overview of Randomized Trials of BCS±RT for DCIS Patient Subset Identified A Priori As Potentially At Low Risk:

Low Nuclear Grade, Negative Margins, Path Tumor Size < 20 mm


Solin, Cancer, 2005

EXCISION PLUS RADIATION FOR DCIS:

RESULTS FROM INTERNATIONAL COLLABORATIVE STUDY (n = 1,003)

MULTIDISCIPLINARY MANAGEMENT OF DCIS:

NSAPB B-17 AND B-24

Wapnir, ASCO, 2007

All IBTR Invasive IBTR

RETROSPECTIVE SELECTION CRITERIA FOR TREATMENT

WITH LUMPECTOMY ALONE AND NO RADIATION

Study Criteria Lagios, 1982 Mammo detection, neg. margins, grade I-II Lagios, 1989 Mammo detection, neg. margins, grade I-II, size <2.5 cm Schwartz, 1992 Mammo detection or incidental finding, neg. margins, size <2.5 cm, (?noncomedo) Silverstein, 1992 Patient refusal of radiation treatment Silverstein, 1995 Grade I-II + necrosis Silverstein, 1996 Van Nuys Prognostic Index (VNPI) score 3-4 Silverstein, 1999 Negative margin width >10 mm Silverstein, 2002 Modified VNPI score 4-6 Silverstein, 2010 Modified VNPI score 4-6 or score 7 margins >3 mm NCCN, 2014 “Low risk” – Not otherwise defined

RESULTS OF LUMPECTOMY ALONE (NO RADIATION) FOR DCIS No. of Actuarial local recurrence (%) patients At 5 yrs At 10 yrs At 15 yrs Retrospective Arnesson 169 16 22 -- Blamey 178 14* 22 -- Cataliotti 105 13 22 -- Cutuli 190 27* 44 -- Hughes 60 18* -- -- Lagios 79 15* 20* 22 Schwartz 256 27* 41* 49* Silverstein 346 19 28 -- Saunders 28 12* 19* 32* Prospective NSABP B-17 405 23* 30* -- EORTC 503 18* 26 -- Swedish 520 19* 30* -- JCRT study 59 12 -- -- ECOG 5194 Low/int grade 572 6 15 -- High grade 99 15 19 -- RTOG 98-04 318 3 -- -- *Estimated from curve

12-GENE DCIS SCORE: ECOG E5194

DCIS Score (0 – 100) evaluated 2 ways:

- Continuous variable

- 3 prespecified risk groups: Low , Intermediate, High

Solin, JNCI, 2013

10-YEAR LOCAL RECURRENCE ACCORDING TO DCIS

SCORE: ECOG E5194 VALIDATION DATA ANY IBE INVASIVE IBE

Solin, JNCI, 2013 Example of patient with DCIS Score = 20

DCIS SCORE: SECOND INDEPENDENT VALIDATION STUDY

Rakovitch E, Oral Abstract, SABCS, December, 2014:

“A large prospectively-designed study of the DCIS Score”

Lumpectomy and RT – tamoxifen vs. anastrozole

NSABP B-35

Lumpectomy and RT + trastuzumab (if Her2 +)

NSABP B-43

Conventional whole breast RT vs. Accelerated

partial breast irradiation (APBI) – NSABP/RTOG

Whole breast radiation + boost – BIG 3-07

SUMMARY OF RANDOMIZED TRIALS FOR DCIS

SUMMARY

Early stage invasive carcinoma

Local control matters

About 1 in 4 local failures results

in a preventable breast cancer death

20-year survival after BCT equal to mastectomy

Margins of resection are important

DCIS

Good long term outcome for BCT/Radiation

Radiation and tamoxifen (ER +) reduce risk

Molecular profiling and biologic subtyping

Evolving strategy for improved risk assessment

and tailored local-regional treatment

BREAST CONSERVATION TREATMENT IN EARLY STAGE...

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