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Radiotherapy
in early and
locally advanced
breast cancer
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Need for RT in Europe
Borras JM et al, Radiother Oncol 2016
Tumor site RT
courses
2012
Increase
in number
2025
Increase
in rate
(%)
Breast 396,891 40,524 10.2
Lung 315,197 56,558 17.9
Prostate 243,669 59,493 24.4
Head&Neck 108,194 13,337 12.3
Rectum 99,493 18,314 18.4
Lymphoma 74,852 9871 13.3
Others ………… …………. …………
About 60%
of the patients
with BC receives
adjuvant RT
After BCS this
rate increases
up to 90-95%
ESTRO-HERO estimation
HERO (Health Economics in Radiation Oncology)
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Early-stage
breast cancer
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Current standard after BCS. WBI
Tangential fields. 3D-CRT Intensity Modulated RT
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HFRT. Review and meta-analysis
• 13 randomized trials
• 8189 patients, early stage (pT1-pT2, pN0)
• Age ≥ 50 years
• Hypofractionation @ versus standard F
• No concomitant chemotherapy
• No study designed for boost (0-74%)
• @ High homogeneity of dose distribution strongly
recommended by ASTRO (± 7%)
Valle LF et al, Breast Cancer Res Treat 2017
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HFRT. Review and meta-analysis
• No difference in:
Local Failure
Loco-Regional Failure
Breast Cancer Specificity Mortality
• Hypofractionaction better for acute toxicity
• No difference in cosmetic outcome
Valle LF et al, Breast Cancer Res Treat 2017
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The winner is: START B trial
CF 1105 pts
HF 1110 pts10 y LRR 10 y OS Cosmesis
50 Gy in 25 fr
2.0 Gy/fr
Mean: 35 days
5.5% 80.8% 45.3%
40 Gy in 15 fr
2.67 Gy/fr
Mean: 21 days
4.3% 84.1% 37.9%
❑ Equivalent local control
❑ Survival benefit
❑ Better cosmesis
P value
0.21
P value
0.042
Haviland C et al, Lancet Oncol 2013
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Elderly patients
Can we push more in HFRT?
UK FAST Forward trial
28.5 Gy (5.7 x 5 f, 1 week)
30.0 Gy (6.0 x 5 f, 1 week)
TP optimised with 3D dose compensation
to ensure
>95% PTV received 95%,
<5% PTV received P105%,
<2% PTV received P107%, and
global Dmax <110% of prescribed dose
Once-weekly HFRT
5.75 Gy x 4 f (17 days)
6 Gy x 6 f (18 days)
5.0 Gy x 5 f (5 weeks)
6.0 Gy x 5 f (5 weeks) 6.25
Gy x 5 f (5 weeks)
6.5 Gy x 5 f (5 weeks)
5.0 Gy x 6 f (6 weeks)
Stereotactic Body RT (SBRT)
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Boost / no Boost EORTC Trial
2,657 patients boost, and 2,661 no boost
WBI 50Gy/5 weeks ± 15/16 Gy boost
20-year follow-up randomised trial
• IBTR: 16% (no boost) vs 12%
• IBTR first failure: 13% (no boost) vs 9%
• No impact on long-term OS
• Severe fibrosis 1.8% (no boost) versus 5.2%
Boost dose better
in the whole group of patients,
but at different level by age
Bartelink H et al, Lancet Oncol 2015
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≤40 years
36.6% vs 24.4%
41-50 years
19.4% vs 13.5%
>60 years
12.7% vs 9.7%
51-60 years
13.2% vs 10.3%
Boost can be omitted in
most patients with
≥ 60years,low-grade, or
favorable biological
profile
Boost / no Boost EORTC Trial
Bartelink H et al, Lancet Oncol 2015
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UK IMPORT HIGH Trial
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Concomitant Boost & HFRT
Whole breast
2.67 Gy x 15
Boost area only
(+0.53 Gy/day)
3.2 Gy x 15
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▪ Edema
▪ Peeling
▪ Dystrophy or atrophy
▪ Hypo or hyper pigmentation
▪ Teleangectasia
▪ Skin thickening
▪ Fibrosis (with nipple and/or breastdisplacement)
Late skin reactions
Breast edema
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GEC-ESTRO
multicentric, phase III,
randomised controlled
trial
ND in 5y- Local Failure
APBI 1.44% vs WBI 0.92%
Equivalent DFS & OS
Partial Breast Irradiation
Strnad V et al, Lancet 2015
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Age at 50
years
DCIS
allowed
Smith BD, ASTRO
IJROBP 2009
Polgar C, ESTRO
Radiother Oncol 2010
PBI ASTRO & ESTRO guidelines
❑ Consider for ASTRO & ESTRO low-risk group,
expecially when receiving Endocrine Therapy
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UK IMPORT LOW Trial2,018 patients, 2007-2010, randomised in 3 arms
40Gy36 Gy
4 Gy 40Gy
Coles CE et al. Lancet 2017
• 1) IBTR Control 1.1%
• 2) IBTR Reduced Dose 0.2%
• 3) IBTR PBI only 0.5%
• Equivalent or fewer adverse effects in 2)&3)
Coles CE et al, Lancet 2017
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Omission of RT after BCSPRIME II TrialCALGB 9343 Trial
IBRT alone 2 vs 20
Axilla alone 0 vs 5
IBRT with axilla 0 vs 1
IBRT with DM 4 vs 6
Total
6 vs 32
ND in:
time to mastectomy
time to DM, BCSS & OS
636 women
Age ≥ 70 yER+
IBRR at 5-years:
1.3% vs 4.1% (p=0.00029)
1326 women
Age ≥ 65 yER+, N0, T<3cm
RR: 1.5% vs 0.5%
DM: 1.0% vs 0.5%
CL: 1.5% vs 0.7%
NC: 4.3% vs 3.7%
Kunkler IH CE et al, Lancet Oncol 2015Hughes KS et al, JCO 2013
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Omission of RT after BCS
No impact on
Overall Survival
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Omission of RT. Low Risk Group
• Older age (?)
• T size <2cm
• pN0
• ER+, low K-67, no LVI, no EIC …….
Braunsteim LZ et al, Breast Cancer Res Treat 2017
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- Luminal A, Ki-67 no >13%
- Age ≥60 years
- Stage I, pN0, IDC, G1-G2,
no EIC & LVI
Ongoing clinical studies
LUMINA
Canada
- Low Oncotype-DX, RS (≤18)
- Age 50-69 years
- Stage I, pN0
IDEA
USA
- Low Risk PAM50 score
- Age 50-75 years
- Stage I, pN0, G1-G2
PRECISION
Boston
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DCIS. Meta-analysis
The Cochrane Collaboration
Author’s ConclusionImplication for practice
Benefit of RT after BCS
Use RT for all women as the overall benefit
was large in all subgroups analysed
Goodwin A et al, 2013
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DCIS. Meta-analysis
Observational Studies and Randomized Clinical Trials (RCTs):
Decreased risk of LR for RT (OR=0.54) and RT + TAM (OR=0.41)
Decreased risk of IBC for RT (OR=0.55) and RT + TAM (OR=0.42)
ND for CBC, DM, and DLi Wang H et al, Oncotarget 2017
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“
• Van Nuys prognostic Index (VNPI), 1990
• VNPI updated, 2003
• MSKCC nomogram, 2010
• VNPI adjusted/genomic grade index, 2011
• Oncotype DX DCIS Score, 2013
• Molecular phenotypes , 2015
DCIS. Prognostic/predictive tools
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Locally advanced
breast cancer
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Post-Mastectomy RT ± RNI
❑ PMRT for pT3 and/or 4 N+ or more
❑ Consider RNI also in N1 (1-3 N+)
cancers and adverse biological
features (<40 years, low or negative
ER, Grase 3, extensive LVI)
ASCO, ASTRO, SSO (Recth A et al, JCO 2016) found
insufficient evidence to define subgroups to which PMRT
should not be used
PMRT to both IMNs and SC-axillary apical nodes in addition
to CW or reconstructed breast in patients with N+
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5-year results WBI WBI + RNI P value
LR Control 94.5% 96.8% 0.020
DFS 84% 90% 0.003
Distant DFS* 87% 92.4% 0.002
OS 90.7% 92.3% 0.070
Lymphedema 4.1% 7.3% 0.004
>G2 toxicity 0.2% 1.3% 0.010
1832 patients, WBI vs WBI + RNI
Eligibility:
1) 1-3 LN+ or >4+ LN+
2) Lumpectomy
3) > 10 nodes dissected
4) >1 of the following (with High Risk LN-)
▪ Grade 3 histology
▪ ER-negative disease
▪ LymphoVascular space Invasion (LVI)
NCIC-CTG - MA-20
Whelan TJ et al, N Engl J Med 2015
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Chronic pain, functional impairment,
psychological distress, poor QoL
Overall incidence: 21.4%
Reported incidence varied in literature
due to the lack of common diagnostic
criteria :
< 5% to > 50%
Lymphedema
Di Sipio T et al, Lancet Oncol 2013
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No RT
B/CW only
B/CW + SC + PAB
B/CW + SC
Type of axillary surgery
Number of LN removed
Regional Node Irradiation
Lack of breast reconstruction
Adjuvant and NA-CT
Body Mass Index (BMI)
Subclinical edema
Cellulitis
Lymphedema. Risk Factors
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Lymph Node draining the arm (ARM node)
Level I-IV and Rotter’s LN
Lymphedema
Wang W et al, Radiother Oncol 2018
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Incidence stratified by lateral border
of supraclavicular field
A. Conventional
B. Modified
C. IMRT
D. Protontherapy
> 2/3
< 1/3
Lymphedema
Chandra RA et al, Int J Radiat Oncol Biol Phys 2015
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AMAROS (EORTC) trial
1425 patients with N+, 744 ALND and 681 ART
Intention to treatment study (85% received treatment)
Median follow-up 6.1 years
Axillary relapse:
- 0.54% (4 patients) in the surgery group
- 1.03% (7 patients) in the RT group
- No differences in OS and DFS
Significant less rate
of lymphedema at 5-years:
13.6% ALND vs 28.0% ART
Donker M et al, Lancet Oncol 2014
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OTOASOR trial (Hungary)
2106 patients with N+, 1054 ALND and 1052 ART
Axillary relapse:
- 2.0% in the surgery group
- 1.7% in the RT group
- No difference in OS and DFS
Any clinical sign of toxicity
at 1-year:
15.3% ALND vs 4.7% RNI
Savolt A et al, Eur J Surg Oncol 2017
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Study Design
POSNOC
2014-….To investigate whether omitting
adjuvant axillary treatment is non-
inferior to ALND or RNI in ≤T2, N+ (1 to 2 macromets)
1900 patients, BCS or mastectomy
BOOG 2013-07
2014-….To investigate whether completion
axillary treatment is non-inferior to
axillary treatment (ALND or RNI)
in ≤T2, up to 3 N+ (micro/macro)878 patients, mastectomy
Trial RNI vs no treatment in N+
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EORTC
phase III
trial 22922/10925
Overall Survival
Distant Disease
Free Survival4004 patients
1996 to 2004
No IM-MS
Irradiation
R
IM-MS
irradiation (50Gy)
Poortmans PM et al,
N Engl J Med 2015
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Irradiation of the left breast
Left circumflex
artery
Left anterior
descending artery
(LAD)
Right coronary
artery
LAD
Years Up 10y 10-14 y 15-19 y >20 y
1973-1982 1.19 1.35 1.64 1.90
1983-1992 0.99 1.02 1.11 1.21
1993-2002 0.97 0.99 - -
2003-2008 1.00 - - -
Cardiac toxicity is mainly due to macrovascular damage, and particularly to the LAD artery
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▪ Deep Inspiration Breath Hold
(DIBH)
▪ Respiratory gating
▪ Prone position (large breast)
▪ PBI
▪ Protontherapy
Goal: “Dose Zero”
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Breast reconstruction
increased from 14.8% in 2000
to 31.9% in 2011
overall
SEER data 2000-2011
Fraiser LL et al, JAMA Oncol 2016
Several factors to be
considered:
General status, co-morbities,
life-style, breast size and
shape, preference
Stage of disease, concomitant
adjuvant treatments
Type of surgery
Type of reconstruction
Type of radiotherapy
Multidisciplinary
Total complication and revision surgery rates
significantly higher for implant reconstruction
after RT
(48.7%; range 38.8 - 58,6%),
than before
(19.6%; range 0.9 – 38.3%)
Berbers J et al, Eur J Cancer 2014
Breast reconstruction and RT
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Geometrical difficulties
Good symmetryBad symmetry
Fair symmetry Capsular contracture
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PMRT after NAC (LR, LRR)Author, year PMRT No PMRT P value
Huang, 2004
stages II, III
stage III
11%
3%
22%
33%
<0.0001
0.006
Garg, 2007 12% 37% 0.001
McGuire, 2007
stages II-III
stage III
5%
7%
10%
33%
0.4
0.04
Nagar, 2011
cT3N0 4% 24% <0.001
Shim, 2014 2% 6% 0.14
Botteri E et al, Br J Surg 2017
NAC not improve survival. Possible advantage in ≤50 years
PMRT should be based on maximal pre-treatment staging
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NSABBP B-18 & B-27
PMRT & NAC: prognostic factors
Mamounas EP et al, J Clin Oncol 2012
Tumor size
>5 vs ≤5 cmP=0.0095
Nodal/breast p-stage
ypN-/pCR- vs ypN-/pCR+
ypN+ vs ypN-/pCR+
P<0.001
EORTC 10994/BIG 1-100
Distant events
First LR event
All events
Molecular subtype
Lum A vs no-Lum A
P<0.0001
p-CR+ vs pCR-
P<0.0001
Gillon P et al, Eur J Cancer 2017
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Study Design Primary End Point
NSABP B51
2013-….RNI vs no treatment in
pCR after NAC
IBC-RFI
ALLIANCE
A011202
2015-….
RNI vs ALND in
persistent N+ after
NAC
IBC-RFI
MA-39
2015-….RNI vs no RNI in low-
risk disease
(biomarkers)
ND in DFS
Trial RNI after NAC in progress
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Inflammatory breast cancer
1-2% of all breast cancer
The use of the trimodality therapy increased up to about 80%
Redness & swelling
Orange peel
Aggressive trimodality treatment,
including PMRT, can be strongly
recommended, regardless
the response to NAC treatment
In the PMRT setting, CTV usually
includes CW and ipsilateral axillary,
infraclavicular, and supraclavicular
lymph nodes (RNI)
RT of the IMN should be considered
in selected cases
Dutch nationwide cancer registry
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• The number of breast cancer will increaseand more cases are expected for RT in2020-2025. More tailored RT is needed inthe era of personalised medicine, withgreat attention to QoL
• RT remains a standard for most earlystages breast cancer. De-intensification indose and volume (PBI) can be consideredfor low-risk groups. Omission of RT canbe proposed in older age patients
Take Home Message (I)
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• New techniques has shown to improvedose homogeneity in the target andreduce the dose to the OARs (less sideeffects). Versatility and flexibility arerequested to face the new challenges inHFRT, PBI, extended LR treatment (RNI)and special cases
• PMRT is the standard in high-risk groups,indipendently from the type of surgery(including reconstructed breast) andresponse to NAC
Take Home Message (II)
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Thank you very
much for your
attention !!!!
Looking in the molecular biology
we will try to give a real tailored
RT treatment
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