BREAST CONSERVATION TREATMENT IN EARLY STAGE...
Transcript of 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 Medical Center
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)
LONG TERM OUTCOMES AT 20 YEARS OR MORE
AFTER STANDARD (WHOLE BREAST) RADIATION
Endpoints Outcome - Local control High - Survival High - Complications Low - Cosmesis High
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
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 Patient age Older Younger Pathology margins of Negative Positive tumor excision or close 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
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
16%
12%
7%
12%
10%
6%
9%
7%
4%
0
P = .097 Adjusted test for trend
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
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
Bartelink, JCO, 2007
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
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
ailu
re a
t 1
0 Y
ea
rs (
%)
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
NSABP B14 AND B20 Age < 50
P = .09
Age ≥ 50
P = .57
ECOG E2197
Lo
ca
l R
eg
ion
al F
ailu
re a
t 1
0 Y
ea
rs (
%)
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
In
cid
en
ce
Ra
te 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)
LOCAL FAILURE AFTER BCT ACCORDING
TO THE USE OF BREAST MRI STUDY
Solin, JCO, 2008
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%
Modified from JCO, 2008
ADD CANADIAN
MRI STUDY
TORONTO
Hwang, Ann Surg Onc, 2009
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
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
Underpowered
for survival,
other endpoints
Consider
comorbidity
SEER, Smith B, JNCI, 2006
T1 N0, Age > 70 years, ER positive
•Local - Lumpectomy plus radiation - Lumpectomy alone - Mastectomy
•Systemic - Tamoxifen
•Optimal treatment strategy is unknown!
TREATMENT OPTIONS FOR DCIS
RATIONALE FOR RADIATION TREATMENT
AFTER LUMPECTOMY FOR DCIS
• All four randomized trials show that radiation reduces the rate of local recurrence after lumpectomy 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
17:41:28 9 Sep 2009Provisional results: subject to revision
(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)
(%)
0 5 10 15Years since randomisation
DCIS: BCS + RT vs. BCSIps. BREAST RECURRENCE (CIS & Inv)
Oxford Overview of Randomized Trials of BCS±RT for DCIS
Darby, JNCI Monograph, 2010
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
17:46:08 9 Sep 2009Provisional results: subject to revision
(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 (
%)
0 5 10 15Years since randomisation
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
Darby, JNCI Monograph, 2010
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, 2013 “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 3 -- -- *Estimated from curve
12-GENE DCIS SCORE: E5194
DCIS Score (0 – 100) evaluated 2 ways:
- Continuous variable
- 3 prespecified risk groups: Low , Intermediate, High
Differences between DCIS Score and 21 Gene Recurrence Score
1. 12 genes in DCIS score are subset of 21 genes in Recurrence Score
2. Calculation algorithm
3. No thresholding for proliferation gene group for DCIS Score
Solin, JNCI, 2013
10-YEAR LOCAL RECURRENCE ACCORDING TO DCIS
SCORE: E5194 ANY IBE INVASIVE IBE
Solin, JNCI, 2013
10-YEAR LOCAL RECURRENCE ACCORDING TO DCIS
SCORE: E5194 ANY IBE INVASIVE IBE
Solin, JNCI, 2013 Example of patient with DCIS Score = 20
MULTIVARIABLE MODELS OF RISK FOR IBE
Hazard Ratio (95% CI) P value Excluding the DCIS Score Tumor size 1.54 (1.14, 2.02) 0.01 Postmenopausal 0.49 (0.27, 0.90) 0.02 Including the DCIS Score DCIS Score 2.41 (1.15, 4.89) 0.02 Tumor size 1.52 (1.11, 2.01) 0.01 Postmenopausal 0.49 (0.27, 0.90) 0.02 For study cohort, surgical margins, grade, comedo necrosis, and DCIS pattern, all p > 0.46. For tamoxifen, p = 0.09. Solin, JNCI, 2013
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
DCIS
Good long term outcome for BCT/Radiation
Radiation and tamoxifen (ER +) reduce risk
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
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