+
Best of SABCS 2012
Radiation Oncology
Catherine Park, M.D.
UCSF Department of Radiation Oncology
+
Content
 Hypofractionation
 APBI
 IORT
 Local Treatment
in Stage IV disease
+
Content
[S4-1] The UK START (Standardisation of Breast
Radiotherapy) Trials: 10-Year Follow-Up Results
 [S4-2] Targeted Intraoperative Radiotherapy for Early Breast
Cancer: TARGIT-A Trial- Updated Analysis of Local
Recurrence and First Analysis of Survival
 [P4-16-08] Intraoperative Electron Radiotherapy in Early
Stage Breast Cancer. A Single-Institution Experience
 [P4-16-03] Patterns of Failure after Accelerated Partial
Breast Irradiation by Consensus Panel Group: A Pooled
Analysis of William Beaumont Hospital and the American
Society of Breast Surgeons Trial Data
 [P4-16-06] Radiotherapy To the Primary Tumor Is Associated
with Improved Survival in Stage IV Breast Cancer

+ Hypofractionated Breast RT
Change in DOSE:
*Hypofractionatedlarger
dose per fraction
*Same time vs. shorter time
versus
versus
+
S4-1: The UK START (Standardisation of
Breast Radiotherapy) Trials: 10-Year
Follow-Up Results

JS Haviland, RK Agrawal, E Aird, J Barrett, P Barrett-Lee, J Brown, J
Dewar, J Dobbs, P Hopwood, P Hoskin, P Lawton, B Magee, J Mills, D
Morgan,JR Owen, S Simmons, MA Sydenham, K Venables, JM Bliss, JR
Yarnold on behalf of the START Trialists
+
Background

International standard adjuvant radiotherapy regimens
following primary surgery for early breast cancer have
historically delivered a high total dose (50Gy) in 25 small daily
doses (fractions)over 5 weeks.

However, randomised trials, including START, indicate that a
lower total dose delivered in fewer, larger fractions (Fr) is likely
to be at least as safe and effective (START Trialists’ Group,
Lancet 2008 & Lancet Oncol 2008).

Here, we report 10-year follow-up of the UK START Trials testing
13- and 15-Fr regimens in terms of local cancer control and late
adverse effects.
+
Methods

Between 1999 and 2002, 4451 women with completely
excised invasive breast cancer (T1-3, N0-1, M0) were
randomised after primary surgery to comparisons of:

50Gy in 25Fr over 5 weeks vs 41·6Gy or 39Gy in 13Fr over 5
weeks (START A)

or 50Gy in 25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks
(START B)

Women were eligible if aged over 18 years and did not have
an immediate surgical reconstruction. ~85% START A and
>90% START B had lumpectomy.

Protocol-specified principal endpoints were local-regional
(LR) tumour relapse and late normal tissue effects.
+
Methods
T1-3, N0-1 M0 breast
cancer
Primary endpoint:
Local-regional relapse
Secondary:
Normal tissue effects
Disease-free and OS
35 UK centers 19992002
Median F/U:
START A- 9.3 yrs
START B- 9.9 yrs
+
Findings: START A
 Median
F/U in survivors is now 9.3 years in START A
and 139 LRs
 In
START A, the 10-year rate of LR relapse was
Treatment
LRR at 10 yrs
95% CI
50 Gy/ 2Gy
7.4%
5.5-10.0
41.6 Gy/ 3Gy
6.3%
4.7-8.5
39 Gy/ 3.2Gy
8.8%
6.7-11.4
+
Findings: START B
 Median
F/U in survivors is now 9.9 years in START B
and 95 LR’s
 In
START A, the 10-year rate of LR relapse was
Treatment
LRR at 10 yrs
95% CI
50 Gy/ 2Gy
5.5%
(95%CI 4.2-7.2)
40 Gy/ 2.67Gy
4.3%
(95%CI 3.2-5.9)
+
Findings
START A
+
Findings
START B
+
Findings: Cosmesis

Clinician assessments suggested lower 10-year rates of any
moderate/marked late normal tissue effects after 39Gy
(43.9%; 95%CI 39.3-48.7) and similar rates after 41.6Gy
(49.5%;95%CI 44.9-54.3) compared with 50Gy (50.4%;
95%CI 45.8-55.3) in START A

and lower rates after 40Gy in START B (37.9%; 95%CI 34.541.5) compared with 50Gy (45.3%; 95%CI 41.7-49.0).

From a planned meta-analysis of START A and the START
pilot trial (Owen et al, Lancet Oncol 2006), the adjusted
estimate of α/β value for tumour control was 3.5Gy (95% CI
1.2-5.7) and for late change inphotographic breast
appearance was 3.1Gy (95% CI 2.0-4.2).
+
Findings
START A: Physicians’ assessment of cosmesis
+
Findings
START B: Physicians’ assessment of cosmesis
+
Conclusions
+
+
Discussion
+
Discussion
Node-negative
clear margins after lumpectomy
exclusion of very large breast size
no boost
10% chemo
+ Accelerated Partial Breast RT
Change in DOSE:
Change in VOLUME:
*Hypofractionatedlarger
dose per fraction
*limited volume
less tissue treated
*Shorter timeless time
versus
+
Intraoperative Radiotherapy Trials
+ [S4-2] Targeted Intraoperative
Radiotherapy for Early Breast Cancer:
TARGIT-A Trial- Updated Analysis of Local
Recurrence and First Analysis of Survival
Lancet 2010
Intrabeam™ for Targeted Intraoperative
Radiotherapy
Intraoperative Technique
Physical Dose Profile
BED= Physical Dose x [1+ (dose/fx) / a/b)]
a/b = 10 (early effects conventional EBRT)
a/b= 1.5 (assumed for TARGiT device)
Distance
Surface
PE probe (Gy)
Conventional EBRT
Physical
Dose
BED
Physical
Dose
BED
0.1 cm
15
165
50
60
0.5 cm
8.75
59
50
60
1.0 cm
5.0
21.7
50
60
Vaidya et al, Annals of Oncol, 2001; 12: 1075-1080
+ Trial schema
+
Findings
+
Update: Methods
 3451
women aged 45 years or older with invasive
ductal carcinoma were enrolled from 33 centres in
10 countries between 2000 and 2012.
 Randomisation
to TARGIT or EBRT arm was done
either before lumpectomy (pre-pathology) or after
lumpectomy (postpathology).

The primary outcome was ipsilateral within breast
recurrence (IBR) with an absolute non-inferiority
margin of 2.5% at 5 years and secondary outcome
was survival.
+
Updated Results

1721 patients were randomly allocated to receive
TARGIT and 1730 to EBRT.

1010 patients have a minimum 4 years follow up and
611 patients have minimum 5 years follow up. 1222
patients with median F/U of 5 years. Primary events
have increased from 13 to 34 since 2010.
+
Updated Results

For the primary outcome of ipsilateral breast
recurrence, the absolute difference at 5-years was
2.0%, which was higher with TARGIT and reached the
conventional levels of statistical significance (p=0.042),
but was within the pre-specified non-inferiority margin;

in prepathology the absolute difference in 5-year IBR
was 1%; in postpathology it was 3.7%.
+
Updated Results

For the secondary outcome, there was a non-significant
trend for improved overall survival with TARGIT (HR =
0.70(0.46-1.07)) due to fewer non-breast cancer deaths
(17 vs. 35, HR 0.47 (0.26-0.84)). Cardiovascular deaths
were 1 vs. 10 and deaths from cancers other than breast
were 7 vs.16.
+
[P4-16-08] Intraoperative Electron
Radiotherapy in Early Stage Breast
Cancer. A Single-Institution Experience

Dall'Oglio S, Maluta S, Marciai N, Gabbani M, Franchini Z,
Pietrarota P, Meliadò G, Guariglia S, Cavedon C. University
Hospital, Verona, Italy
+
Methods
 From
July 2006 to December 2009, 226 patients
suitable for BCT were enrolled in a phase II trial
with IOERT as radical treatment immediately after
surgical resection.
 After
the surgeon temporarily re-approximated the
excision cavity, a dose of 21 Gy using IOERT was
delivered to the tumor bed with a margin of 2 cm
laterally.
+
Methods
+
Methods
+
Methods
+
Methods
+
Methods
+
Results
+
Results
+ ELectron Intraoperative Radio
Therapy= ELIOT
Fig 1. After the upper-outer quadrantectomy of left
breast, a medial glandular flap is performed. The breast
is separated, superficially by the skin, and deeply by the
pectoralis muscle.
Fig 2. The mobilization of the breast target is
concluded preparing the lateral glandular flap.
Fig 3. The gland is reconstructed over the aluminum
and lead disks to expose the correct portion of the breast
to be irradiated. The disks (outlined) appear between
the restored breast and the pectoralis muscle.
Intra…Veronesi et al Surgery September 2006
+ Electrons Intraoperative Therapy: ELIOT Trial
Fig 4. Sagittal plane of the breast. The sterile collimator
of the linear accelerator is introduced through the skin
incision and placed directly in contact with the breast
target. The aluminum and lead disks are located between
gland and pectoralis muscle, exactly on the line of the
collimator. The disk size must be at least equal or superior
to the breast target size.
Veronesi et al, Ann Surg 2005;242: 101–106
+
ELIOT results 2010
 1822
pts with ELIOT from Jan 2000 to Dec 2008
 1800
pts received 21 Gy rx to 90% isodose
 1381
received endocrine therapy
 176
chemotherapy alone
 198
chemotherapy and endocrine therapy
 67
had no adjuvant treatment
 58
women since 2005 received Herceptin
 Mean
f/u 36.1 months
Veronesi, Br Can Res Tr 2010
+ ELIOT results 2010
Factor
number
%
Age <50
368
20.2
Lobular Ca
202
11.1
Size 2-5 cm
261
14.3
Positive nodes
517
28.4
Grade 3
459
25.2
Peritumoral vascular 294
invasion
16.1
ER negative
194
10.6
HER2 +
173
9.5
Lum A
648
35.6
Lum B
977
53.6
Her2+
53
2.9
Basal
137
7.5
+ ELIOT results 2010
Factor
number
%
Annual %
True local recurrence
42
2.3
0.77
Ipsilateral breast ca
24
1.3
0.44
Regional metastasis
18
1.0
0.33
Contralateral ca
19
1.0
0.35
Distant metastasis
26
1.4
0.47
Other cancer
33
1.8
0.60
Death as first event
11
0.6
0.20
Any first event
171
9.4
3.12
Deaths from br ca
28
1.5
0.45
Deaths from other
12
0.7
0.20
Unspecificed death
6
0.3
0.10
Any death
46
2.5
0.76
+ ELIOT results 2010
Factor
number
%
Mild fibrosis
32
1.8
Severe fibrosis
2
0.1
Lyponecrosis
78
4.2
Hematoma
101
5.5
Edema
24
1.3
Pain
13
0.7
Wound infection
24
1.3
Seroma
235
12.9
No side effects
1434
78.7
1 side effect
292
16.0
2 side effects
76
4.2
3 side effects
16
0.9
+
ELIOT Multivariate Model for LR
Factor
HR
P value
Age <50
2.10 (1.18–3.74)
0.01
Size >2.0
2.29 (1.02–5.15)
0.04
Lobular histology
1.89 (0.90-3.95)
0.09
Lum A (ER+ or PR+,KI-67<14%, Her2-)
1.00
Lum B (ER+ or PR+, KI-67>14% or Her2+) 3.46 (1.52–7.90)
0.003
Her2+ (ER- and PR-, Her2+) (n=53)
5.68 (1.72–18.8)
0.004
Basal (ER-, PR-, Her2-)
5.26 (1.84–15.0)
0.002
+
ELIOT trial results 2010
+
ELIOT trial results 2010
+
+How much is tumor biology driving local
recurrence risk?
1.2 cm, grade 1, ER/PR +, Her2+
“luminal” type
1.2 cm, grade 3, ER/PR-,Her2“basal” type
Subtype
LR at LR at LR at LR at
5 yrs1 5 yrs2 5 yrs3 8 yrs4
LR at
10
yrs5
LR at
10
yrs6
Lum A
0.8%
2%
2.3%
3.5%
8%
ns
Lum B*
1.5%
3%
--
13.4%
^8%
ns
HER 2*
8.4%
13%
4.6% 29.2%
21%
ns
Basal
7.1%
21%
3.2%
14%
22%
1Nguyen
5.8%
et al, JCO 26:2373, 2008 Harvard
* Pre-Herceptin era
et al, JCO 27: 4701, 2009 Australian
3Freedman et al, Cancer 115: 946, 2009 FCCC
4Albert et al, IJROBP 77:1296, 2010: Stage T1a,b N0 BCT 62% MDAH
5Voduc et al, JCO 28: 1684, 2010 British Columbia and UNC; ^Lum Her2
6Haffty et al, JCO 24:5652, 2006 Yale
2Millar
CONSENSUS STATEM ENT
ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROM
THE AMERICAN SOCIETY FOR RADIATION ONCOLOGY (ASTRO)
BENJAMIN D. SMITH, M.D.,* y DOUGLAS W. A RTHUR, M.D.,z THOMAS A. BUCHHOLZ, M.D.,y
BRUCE G. HAFFTY, M.D.,x CAROL A. HAHN, M.D.,k PATRICIA H. HARDENBERGH, M.D.,{
THOMAS B. JULIAN, M.D.,# L AWRENCE B. M ARKS, M.D.,** DORIN A. TODOR, PH.D.,z
FRANK A. V ICINI , M.D.,yy TIMOTHY J. WHELAN, M.D.,zz JULIA WHITE, M.D.,xx JENNIFER Y. WO, M.D.,kk
{{
AND JAY R. HARRIS, M.D.
* Radiation Oncology Flight, Wilford Hall Medical Center, Lackland AFB, TX; yDepartment of Radiation Oncology, TheUniversity of
Texas M. D. Anderson Cancer Center, Houston, TX; zDepartment of Radiation Oncology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA; xDepartment of Radiation Oncology, University of Medicineand Dentistry of New Jersey –
Robert Wood Johnson Medical School, New Brunswick, NJ; k Department of Radiation Oncology, Duke University Medical School,
Durham, NC; { Shaw Regional Cancer Center, Veil, CO; #Department of Human Oncology, Allegheny General Hospital, Pittsburgh,
PA; ** Department of Radiation Oncology, University of North Carolina Medical School, Chapel Hill, NC; yyDepartment of Radiation
Oncology, William Beaumont Hospital, Royal Oak, MI; zzDepartment of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON,
Canada; xxDepartment of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; kk Harvard Radiation Oncology
Residency Program, Boston, MA; and { { Department of Radiation Oncology, Dana-Farber Cancer Instituteand Brigham and Women’s
Hospital, Boston, MA
IJROBP 2009
Purpose: To present guidance for patients and physicians regarding the use of accelerated partial-breast irradia-
+
ASTRO “Suitable Group”
Factor
ALL of the following must be present
Age >=60 years
Tumour size <=2cm
Margins Negative by at least 2mm
Grade Any
ER status Positive
Multicentricity Single tumour
Multifocality Clinically unifocal <2.0 cm
Histology Invasive Ductal or favourable subtype
Extensive Intraductal Component (>25% DCIS) Absent
Lymphovascular invasion Absent
Lymph nodes Node Negative
5
2
+
ASTRO “Cautionary Group”
Factor
Any of these should invoke caution
Age 50-59 years
Tumour size 2.1 – 3cm
Margins Close < 2mm
ER status Negative
Multifocality Clinically Unifocal, total size 2.1-3.0cm
LVSI Limited/focal
Histology Invasive Lobular
Pure DCIS <3 cm
Extensive Intraductal Component (>25% DCIS) <3 cm
Lymphovascular invasion Limited or Focal
+
ASTRO “Unsuitable Group”
Factor
Any of the following must be present
Age <50 years
Tumour size > 3 cm
Margins Positive
ER status Negative
Multicentricity More than 1 tumour
Histology Invasive Lobular
Extensive Intraductal Component (>25% DCIS) Present
Lymphovascular invasion Extensive
Lymph nodes Positive
+ [P4-16-03] Patterns of Failure after
Accelerated Partial Breast Irradiation by
Consensus Panel Group: A Pooled Analysis
of William Beaumont Hospital and the
American Society of Breast Surgeons Trial
Data

Wilkinson JB, Beitsch PD, Arthur D, Shah C, Haffty BG, Wazer D,
Keisch M, Shaitelman SF, Lyden M, Chen PY, Vicini FA. Oakland
University William Beaumont School of Medicine, Royal Oak, MI;
Dallas Surgical Group, Dallas, TX; Massey Cancer Center, Virginia
Commonwealth University, Richmond, VA; Washington University
School of Medicine, St. Louis, MO; Cancer Institute of New Jersey,
Robert Wood Johnson Medical School, Camden, NJ; Tufts Medical
Center and Rhode Island Hospital/Brown University, Boston, MA;
Cancer Healthcare Associates, Miami, FL; University of Texas M.D.
Anderson Cancer Center, Houston, TX; Biostat International, Inc.,
Tampa, FL; Michigan Healthcare Professionals/21st Century
Oncology, Farmington Hills, MI
+
Background:
 To
determine six-year outcomes and patterns of
failure following accelerated partial breast
irradiation (APBI) within a pooled patient
population from William Beaumont Hospital (WBH)
and the American Society of Breast Surgeons
(ASBrS) MammoSite® Registry Trial.
+
Methods:

2,127 cases of early-stage breast cancer were treated using
APBI (WBH: n=678; ASBrS: n=1,449).

Three forms of APBI were used at WBH (interstitial, n=221;
balloon-based, n=255; or 3D-CRT, n=206) while all Registry
Trial patients received balloon-based brachytherapy.

Patients with complete coding necessary for ASTRO
Consensus Panel (CP) group assignment (n=1,813) were
divided into suitable (n=661, 36.5%), cautionary (n=850,
46.9%), and unsuitable (n=302, 16.7%) categories.

Tumor characteristics, clinical outcomes, and patterns of
failure were analyzed according to CP group.
+
Methods:
+
Methods:
+
Results:
+
Results:

Median follow up was 59.4 months.

Six-year rates of ipsilateral breast tumor recurrence (IBTR),
regional nodal failure (RNF), and distant metastasis (DM) for
the whole cohort were 3.2%, 0.7%, and 1.1%, respectively.

Elsewhere failures (EF) were the predominant mode of inbreast recurrence for each CP group (suitable: 2.3%,
cautionary: 2.5%, unsuitable: 4.9%, p=0.16) as compared to
true recurrences (TR) near the lumpectomy bed (suitable
0.9%, cautionary: 1.5%, unsuitable: 0.8%).

No statistical difference in combined rates of ipsilateral
recurrence (TR+EF) were observed between the three
consensus panel groups (suitable: 3.2%, cautionary: 4.1%,
unsuitable: 5.7%, p=0.25).
+
Results:

On multivariate analysis, no factor was associated with risk of
true recurrence while ER negative status (OR: 4.13, p<0.01)
and a positive/close margin (OR: 2.70, p=0.02) were
associated with increased rates of elsewhere failure.
+
Conclusions
Factors specifically associated with IBTR following breast
conserving therapy include young age at diagnosis,
involved or close surgical margins, increased tumor size,
ER negative receptor status, high grade histology, lymph
node involvement, extensive intraductal disease, and
lymphovascular space invasion.
These factors have not necessarily been shown, however, to
be specific predictors of elsewhere failure only for women
treated with limited-field radiotherapy.
+
Conclusions
The risk factors identified in the ASTRO CS groups may
portend for an increased risk for treatment failure
following breast conservation, regardless of method of
adjuvant radiotherapy. As a result, clinicians and patients
are forced to rely on recommendations based upon
extrapolated data from risk factors associated with
IBTR following whole breast irradiation and not the
underlying scientific concept of localizing radiation only
to the tumor bed region (i.e., APBI).
+
[P4-16-06] Radiotherapy To the Primary
Tumor Is Associated with Improved
Survival in Stage IV Breast Cancer

Morgan SC, Caudrelier J-M, Clemons MJ. University of
Ottawa, ON, Canada; The Ottawa Hospital Cancer Centre,
Ottawa, ON, Canada
+
Background:
 In
patients found to have metastatic disease at the time
of breast cancer diagnosis, the role of local therapy is
undefined. Numerous retrospective analyses have
suggested that surgery and/or external beam
radiotherapy (EBRT) directed at the primary tumor may
improve overall survival (OS). All these analyses,
however, are subject to significant selection bias. The
current retrospective analysis of a large registry
dataset attempts to limit the effect of this bias.
+
Methods:

The study population consisted of women in the Surveillance,
Epidemiology, and End Results (SEER) program database
diagnosed with stage IV breast cancer between 1988 and 2009.

Only those patients for whom surgery to the primary tumor was
recommended but was not undertaken (due to patient refusal or
other uncategorized reasons) were included.

In this population of patients deemed candidates for surgery, the
association between receipt of primary tumor-directed EBRT and
overall survival was studied. Descriptive statistics were used to
characterize the study population. OS was estimated using the
Kaplan-Meier (KM) method. Univariate and multivariate Cox
regression were used to identify factors associated with OS.
+
Results:

A total of 3,529 cases were analyzed. EBRT was received in
768 cases. Median age at diagnosis was 68 years (IQR, 56-79
years). Median follow-up by reverse KM estimate was 98
months (range, 0-252 months).

On univariate analysis, EBRT was associated with improved
OS (hazard ratio 0.80, 95% CI 0.74-0.87, p<0.001). 1-year, 3year, and 5-year OS was 56.9%, 24.2%, and 10.7%
respectively in those receiving EBRT and 44.3%, 16.6%, and
7.2% respectively in those not receiving EBRT.

Median OS in those receiving EBRT was 15 months
compared to 7 months in those not receiving EBRT.
+
Results:

In a multivariate Cox model taking into account receipt of
EBRT, age at diagnosis, year of diagnosis, ethnicity, number
of primary cancers, estrogen and progesterone receptor
status, histologic grade, and size of primary tumor, EBRT
remained significantly associated with improved survival
(hazard ratio 0.86, 95% CI 0.76-0.97, p=0.011).
+
Conclusions:

In a population of women presenting with metastatic breast
cancer, all of whom were deemed candidates for surgery to
the primary tumor but who did not undergo surgery, receipt
of EBRT was associated with improved OS. The observed 8month absolute difference in median OS is clinically
significant. This analysis could not account for performance
status, extent of metastatic disease, co-morbidities, use of
systemic therapies, and other potentially confounding factors.
Only randomized studies, such as the Eastern Cooperative
Oncology Group E2108 trial currently underway, will be able
to definitively assess the value of local therapy directed at the
primary tumor in this setting.
+
ECOG 2108
+
+
+
+
+
The End