2. The more things change, the more they remain the
same:
The target, dose, fractionation and delivery
modalities are all changing in breast cancer.
Yet, some of the key questions of yesterday still
remain!
3. NEW STANDARDS OF CARE IN
RADIOTHERAPY OF BREAST CANCER
Whole breast RT followed by tumor bed boost
APBI
Conformal RT
IMRT & VMAT
Hypofractionated RT
Changing indications for post-mastectomy
radiotherapy (chest wall & nodal)
Prone breast RT
4. BCS+RT
Mastectomy is no longer a standard of care in
breast cancer surgery
BCS is possible in all EBC and is also practised in
LABC
Whole breast RT is compulsory in BCT
Results of BCS+RT and mastectomy are equivalent
Local control rates are also significantly improved
by use of boost to tumor bed
6. The pooled meta-analysis of 15 RCTs
shows a threefold reduction in local
failure & a small but significant
BCS+RT VS BCS improvement in OS with RT after BCS
Vinh-Hung et al. JNCI ( 2004);96:115-121
7. EBCTCG META-ANALYSIS (LANCET 2000)
Meta-analysis of 10 Breast cancer mortality
and 20 yr results of 40 was significantly
RCTs of EBC. reduced
N=20 000 However, mortality due
50% node positive to other causes was
significantly increased.
Local recurrence after
BCS was reduced by Absolute increase in
approximately 2/3 with 20-yr survival was 2-
RT, irrespective of type 4% (except those
of RT and stage. women at very low risk
of recurrence).
8. EBCTCG META-ANALYSIS (LANCET 2005)
78 RCTs of EBC. 15-yr breast cancer
N= 42 000 mortality was
significantly
7300 had BCS
reduced, from 35.9% to
Local recurrence rate 30.5%
at 5 years, after BCS
Overall mortality
was reduced by post-
op RT from 26% to 7%. reduction with RT was
5.3% at 15-yrs.
Similar proportional
benefit of RT in ALL
stages. Absolute
benefit varies with the
actual risk, according
to stage.
9. BREAST CONSERVATION THERAPY:
NODE NEGATIVE DISEASE
5 yr gain 16.1% 15 yr gain 5.1%
LR OS
EBCTCG Lancet 2005,vol 366, 2093
10. BREAST CONSERVATION THERAPY:
NODE POSITIVE DISEASE
LR OS
5 yr gain 30.1% 15 yr gain 7.1%
EBCTCG Lancet 2005,vol 366, 2093
11. EBCTCG META-ANALYSIS (LANCET 2011)
17 RCTs of BCS+RT vs 15-yr breast cancer
BCS alone mortality was
N= 10 801 significantly
(pN0=7287, pN+=1050 reduced, from 25.2% to
) 21.4%
ANY recurrence rate at Similar proportional
10 years, after BCS benefit of RT in ALL
was reduced by post- stages. Absolute
op RT from 35% to benefit varies with the
19.3%. actual risk, according
to stage.
12.
13. BOOST VS NO BOOST
EORTC 22881-10882 TRIAL
Bartelink et al
14. Planning of boost is largely dependant on localisation
method and modality used
Many centres practise clinical planning, especially if
electrons are to be used
CT based planning, though preferable, is also
problematic
Cavity location is not always clear.
Also the shape and size of the cavity will
change, depending on when the image is taken
15. SEROMA CONTOURING GUIDELINES
STV (Seroma Target
Volume)= tumor cavity
CTV= STV+1cm
(EDITED from skin and
chest wall by 5mm)
PTV=CTV+1cm
STV to EXclude breast
tissue stranding, but
INclude surgical clips (if
present)
Wong et al
16. BOOST MODALITIES
En-face electrons
HDR brachytherapy
3DCRT/IMRT/VMAT
IMPT
Modulated electrons (MERT)
Electrons are still the commonest and simplest
modality. But dosimetrically the most inferior!
HDR brachytherapy is a labour
intensive, cosmetically demanding, but
dosimetrically excellent alternative for deep-seated
tumors. (>3cm from skin)
18. BREAST CONTOURING GUIDELINES
Because more and more centres are doing
conformal CT-based planning for breast
cancer, contouring guidelines for the intact breast/
chest wall are also increasingly necessary.
The RTOG has come up with a Breast Cancer
Atlas.
30. APBI
Twin rationale:
(1) Most breast cancer recurrences occur in the index
quadrant.
(2) Many patients cannot come for prolonged 5-6
week adjuvant radiotherapy for logistic reasons.
31. APBI: INDICATIONS
(ASTRO RECOMMENDATIONS)
Suitable outside clinical trial Suitable only in a clinical
(ALL of) trial
Age>60 years (ANY of)
BRCA negative
Age 50-59 years
T1N0M0 (pT<2cm)
BRCA negative
EIC negative
T1/2,N0,M0 (pT2-3 cm)
Unifocal
EIC <3cm
IDC/ favourable histology
Unifocal
Margin negative (>2mm)
ILC
LCIS negative
Margin close (<2mm)
ER positive
ER negative
32. ASTRO: “UNSUITABLE” FOR APBI
ANY OF:
T>3cm/T4 or N+
BRCA mutated
High grade
LVSI extensive
EIC+ve (>3cm)
Multifocal disease (contraindication to BCS per se)
Margin positive
Received neoadjuvant chemotherapy
42. HDR INTERSTITIAL BRACHYTHERAPY:
RESULTS
Institution Dose Dose Rate Ipsilateral Cosmesis &
breast Complications
recurrence
rate
William 32-34 HDR 2.1% (5-yr) >90% achieved good
Beaumont Gy/8-10# to excellent cosmesis
Hospital,
USA 50 Gy LDR 0.9% (5-yr)
Ochsner 32-34 HDR 8% 75% achieved good to
Clinic, USA Gy/8-10# excellent cosmesis
50 Gy LDR
London 37.2 HDR 16.2% at 5 Median overall
Regional Gy/10# yrs* cosmetic score 89%.
Cancer
Centre,
Ontario,
Canada
43. HDR INTERSTITIAL BRACHYTHERAPY:
RESULTS
Institution Dose Dose Rate Ipsilateral Cosmesis &
breast Complications
recurrence
rate
National 30.3-36.4 HDR 6.7% Excellent to good
Institute of Gy/7# cosmesis in 84.4%.
Oncology,
Hungary
Tufts New 34 Gy/10# HDR 6.1% (5-yr 89% had excellent
England, actuarial) cosmesis at 5 years.
USA
Guy’s 55 Gy LDR 37%* Cosmesis good to
Hospital, excellent in 85%.
London
*= inappropriate selection of patients for APBI
44. MAMMOSITE:
RESULTS
Institution Dose Ipsilateral Cosmesis &
breast Complications
recurrence
rate
American Society of 34 Gy/10# 1.79% 3-yr Good-excellent cosmesis
Breast Surgeons actuarial LRR in >93%.
Mammosite Breast
Brachytherapy
Registry trial (97
institutions)
Rush University 34 Gy/10# 5.7% (crude) Good-excellent cosmesis
Medical Centre, in 93%.
Chicago, USA
45. IORT:
RESULTS
Institution Dose Modality Ipsilateral Cosmesis &
breast Complications
recurrence
rate
European 21 Gy Electrons 1% Mild/severe fibrosis in
Institute of 3%.
Oncology,
Milan
State 15-20 Gy 120 kV X 29% Acceptable
University of rays
Buffalo, USA
University 20 Gy 50 kV X 0% Acceptable
College, rays
London
(TARGIT)
48. IMRT BREAST: WHY?
Dosimetric advantages include:
(1) better dose homogeneity for whole breast RT
(2) better coverage of tumor cavity
(3) feasibility of SIB
Forward planned IMRT (field-in-field) is preferred as
it is simple and effective.
52. IMPORT TRIALS
(PHASE III RCTS FROM UK)
IMPORT High: (2008-ongoing) IMPORT Low: (2006-2010)
To test dose-escalated IMRT in To test PBI by IMRT in low-
high-risk EBC after BCS risk EBC after BCS
High risk by v/o (ANY) (ALL) IDC/no ILC/pN0/no
N+/grade III/T>2/NACT LVE/pT<3cm/unifocal/grade
received/margin<5mm/age 18- I,II or III/margin>2mm
49 yrs/LVE+ 3 arms:
3 arms: WBRT (15#/3 weeks)
WBRT followed by sequential WBRT +PBI (each 15#/3
boost (56 Gy/23#) weeks)
WBRT with SIB (48Gy/15#) PBI (15#/3 weeks)
WBRT with SIB (53Gy/15#)
Primary endpoint: Local
Primary endpoint: Breast fibrosis control (ipsilateral)
53. HYPOFRACTIONATED RT
Started as an empirical practice in government-run
health care systems of UK and Canada
Initially, a purely logistical exercise to reduce
treatment duration & create machine space
Recently, 2 large trials, START-A and START-B,
have validated that clinically as well,
hypofractionated RT is safe and effective.
In fact, even while delivering a lower BED, the
hypofractionated regimens have shown a survival
advantage over conventional fractionation!
54. START-A: (1998-2002) Locoregional relapse
N=2236 rates were 3.6%, 3.5%
and 5.2%, respectively
EBC (pT1-T3a, pN0-
N1, M0)
BCS=1900 (85%) & Late effects, based on
MRM=336 (15%) photographs and patient
assessments, were
3 arms:
significantly lower with 39
50 Gy/25#/5 weeks Gy as compared to 50 Gy
41.6 Gy/13#/5 weeks This trial estimated α/β of
39 Gy/13#/5 weeks breast cancer as 4.6Gy
for tumor control and
Median FU=5.1 years 3.4Gy for late change in
photographic appearance.
Lancet Online. March 19,2008
55. START-B: (1999-2001) Locoregional relapse
N=2215 rates were 3.3% and
2.2%, respectively
EBC (pT1-T3a, pN0-N1,
M0)
BCS=2038 (92%) & Absolute differences in
MRM=177 (8%) locoregional relapse was -
0.7% (95%CI -1.7% to
2 arms:
0.9%), meaning that with
50 Gy/25#/5 weeks
40Gy the relapse rate
40 Gy/15#/3 weeks would be at most 1%
worse and at best 1.7%
Median FU=6 years BETTER!
Lancet Online. March 19,2008
56. HYPOFRACTIONATION FROM THE
RADIOBIOLOGIC VIEWPOINT
UK-FAST: (2004-2007) Primary end-point was 2 yr
N=915 change in photographic
appearance of breast
Favourable EBCs after BCS
(age>50 yrs, pT<3cm, pN0) 3-yr physician assessed
moderate to marked breast
adverse effects were 9.5%,
3 arms: 11.1% and 17.3%
50Gy/25$/5 weeks respectively.
28.5Gy/5#/5 weeks (once-
weekly) Conclusion:At 3 yrs median
30Gy/5#/5 weeks (once- FU, 28.5Gy/5# (@5.7Gy/#)
weekly) is comparable to 50Gy/25#
for breast adverse effects
and significantly milder than
Median FU=37.3 months 30Gy/5# (@6Gy/#)
Radiotherapy & Oncology. Epub.2011
57. CHANGING INDICATIONS OF PMRT
New indications include:
Any AXLN +ve
High grade tumors
LVE
PNI
Age <45-50 years
pT>2cm
Scoring systems are often used.
58. PN1 VS PN2 FOR CHEST WALL RT
Classically, pN2 disease (>=4 positive axillary
nodes) was the indication for postmastectomy chest
wall RT
Subgroup analysis of the DBCG 82 b&c trials
(2007) suggested SIMILAR survival benefit of
PMRT for 1-3 vs 4+ LN.
The St Gallen Consensus (2007) is to treat the SCF
even for pN1 (1-3 positive axillary nodes)
The SUPREMO trial evaluated the benefit of PMRT
in 1-3 axillary lymph node positive patients.
59.
60. SUPREMO TRIAL
(SELECTIVE USE OF POSTOPERATIVE
RADIOTHERAPY AFTER MASTECTOMY)
Started 2006. Expected to
complete end-2012.
N=1600 (planned); 1295 Objective: To determine the
randomised so far* overall survival of
intermediate risk patients
pT1-T3 (+/- multifocal ds), treated with post-op RT
pN0-N1 (not more than 3
AXLN positive), M0 ,post-
MRM Primary endpoint: OS, acute
No bilateral breast cancer, & late morbidities
margins clear (at least 1mm),
no IMC nodes Secondary endpoints:
Chemotherapy as required Locoregional recurrence
rates, metastasis-free
survival, DFS, QoL, cost-
2 arms: effectiveness
Standard RT to chest wall &
SCF
Observation
*personal communication
61. IS THERE A ROLE OF AXILLARY NODAL RT?
Axillary nodal RT is no longer indicated if complete
axillary dissection (>10 LN sampled) has been
performed.
Axillary nodal RT significantly adds to the
lymphoedema morbidity
The only possible indications today are:
(1) incomplete/ no axillary dissection
(2) positive axillary nodes WITH extracapsular
extension (ECE)/ perinodal extension (PNE)
62. IS SCF RT REQUIRED
AT ALL?
Studies suggest that isolated SCF recurrences are
uncommon, for both pN1 and pN3 disease
The main risk for pN3 disease, is not SCF
recurrence but distant metastasis
63. PRONE BREAST RT
Suitable for pendulous
breasts, where breast-only
RT is required.
Results in significantly better
coverage of the breast and
significant reduction of dose
to the ipsilateral lung.
Heart dose remains
unchanged.
BUT there is significantly
more grade 1-2 dermatitis
AND setup error.
Varga et al