LOCO-REGIONAL TREATMENT

Principles of breast radiation therapy

Roberto Orecchia

European Institute of Oncology, Milan, Italy

DISCLOSURE OF INTEREST
I state that I have No disclosures to declare
PRINCIPLES OF RADIATION THERAPY

Radiation Therapy (RT) is a clinical modality dealing with use of ionizing radiations in the treatment of
patients with malignant neoplasias.
The aim of RT is to deliver a precisely measured dose of irradiation to a defined tumour volume with a
minimal damage as possible to surrounding healthy tissue, resulting in eradication of tumour, a high quality
of life, and prolongation of survival at competitive cost.
In addition to curative efforts, RT plays a major role in the effective palliation or prevention of sympotms of
the disease: pain can be alleviated, luminal patency can be restored, skeletal integrity can be preserved, and
organ fuction can be reestablished with minimal morbidity.
To integrate the various disciplines and provide better care to patients, it is extremely important for the
radiation oncologists to cooperate closely with specialists in other fields.

When a radiation oncologist administering RT to a patient, five fundamental questions must be answered:
• What is the indication for RT?
• What is the goal of RT?
• What is the planned treatment volume?
• Hhat is the planned treatment technique?
• What is the planned treatment dose?
NEED FOR RT IN EUROPE. ESTRO-HERO ESTIMATION

Tumor site RT courses Increase Increase in

(2012) in number (2025) rate (%)
About 60%
Breast 396,891 40,524 10.2 of the patients
Lung 315,197 56,558 17.9 with BC receives
adjuvant RT
Prostate 243,669 59,493 24.4
Head&Neck 108,194 13,337 12.3
Rectum 99,493 18,314 18.4
After BCS this
rate increases
Lymphoma 74,852 9871 13.3 up to 90-95%
Others ………… …………. …………

Breast cancer is the first or second cancer treated by RT in all the European Countries

Borras JM et Al. Radiother Oncol 2016

 Early-stage

breast cancer
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2011
LOCAL RELAPSE AFTER WHOLE BREAST IRRADIATION

• Between 1975 and 1990: from 8.5% to 19.7%

• Between 1991 and 1998: from 2.8% to 5.7%
• Between 1999 and 2005: from 1.0% to 0.4%

IEO Milan
BCS + EBRT (50+10 Gy)
2784 pts b/n 2000-03
LF at 5-y: 1.1% (Ann Oncol, 2010)

IEO Milan ELIO T trial

BCS + EBRT
601 pts b/n 2001-2007
LF at 5-y: 0.4% (Lancet Oncol, 2013)
WHOLE BREAST IRRADIATION (WBI) AFTER BCS

WBI is the standard.

Conventional fractionaction implies 25-30 sessions (50 Gy total dose, eventually plus boost 10-16 Gy)
BOOST VERSUS NO BOOST. EORTC TRIAL

≤40 years 41-50 years

24.4% vs 36.6% 13.5% vs 19.4%

Boost dose can be

omitted in most
over 60 years
51-60 years >60 years patients, with low-
10.3% vs 13.2% 9.7% vs 12.7% grade or favorable
biological profile

IBTR boost: 12% versus 16% No boost. Boost better in the whole group, bur at different level by age

Bartelink H et Al. Lancet Oncol 2015

HYPOFRACTIONACTION (HFRT)
• 13 randomized trials
• 8189 patients, early stage
• Age ≥ 50 years
Whole breast 2.67 Gy x 15
• High homogeneity in dose distribution strongly recommended
(ASTRO ± 7%)

START B Trial

Boost area only 3.2 Gy x 15

Equivalent in Local & Loco-Regional Control. No difference in Survival and cosmetic outcome. To-day HFRT
is recommended as a new parallel standard in most patients
Valle LF et Al. Breast Cancer Res Treat 2017; Haviland JS et Al. Lancet Oncol 2013
CAN WE PUSH MORE IN HYPOFRACTIONACTION?
UK IMPORT HIGH TRIAL

Phase III randomised trial of RT dose escalation in women at higher than average risk of LR after BCS.
Useful also to test the efficacy of IGRT as highest quality treatment
Coles C & Yarnold Y. Clin Oncol 2006; Bhattacharya IS et Al. Radiother Oncol 2019
 LATE SKIN REACTIONS

▪ Edema
▪ Peeling
▪ Dystrophy or atrophy
▪ Hypo or hyper pigmentation
▪ Teleangectasia
▪ Skin thickening
▪ Fibrosis (with nipple and/or breast displacement)
In general, RT is very well tolerated by most patients and does not significantly impair their daily
activities.
Acute side effects are common in occurrence, self-limiting, and resolve within 4-6 weeks. Skin
reaction dominate the early toxicity profile.
Late sequelae can be divided in 2 groups: the more common effects on the appearance of the breast,
and those that very uncommon but severe in consequences, as brachial plexophaty, lymphedema,
cardiac morbidity.
 IRRADIATION OF THE LEFT BREAST
Right coronary artery Left circumflex artery
Left anterior descending 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 mailnly due to macrovascular damage, and particularly to the LAD artery.
RT increases the rate of major coronary events by 7.4% per Gy, with no apparent threshold
(0-5 Gy HR 1.08; >5-15 Gy HR 1.32; >15 Gy HR 1.63; the double with concurrent CT-RT).
IRRADIATION OF THE LEFT BREAST
GOAL: DOSE ZERO
▪ Deep Inspiration Breath Hold (DIBH)
▪ Respiratory gating
▪ Prone position (large breast)
▪ PBI
▪ Protontherapy
PARTIAL BREAST IRRADIATION (PBI)

APBI is a localized form of RT delivered after lumpectomy to only the part

of the breast where the tumour was removed.
This procedure requires close collaboration between the surgeon and the
radiation oncologist.
When compared with WBI, APBI offers several benefits, including reduced
treatment time and sparing healthy tissue.

Correa C et Al. Pract Radiat Oncol 2017

UK IMPORT LOW TRIAL

1) IBTR Control 1.1%

2) IBTR Reduced Dose 0.2%
3) IBTR PBI only 0.5%
Equivalent/fewer adverse effects

36 Gy 40Gy
40Gy
4 Gy

Coles CE et Al. Lancet 2017

 OMISSION OF RT AFTER BCS
CALGB 9343 Trial PRIME 2 Trial
IBRT aloneND in: 2 vs 20 IBRR at 5-years:
Axilla alone
time 0 vs 5
to mastectomy
IBRT with axilla 0 vs 1
time to DM, BCSS & OS 1.3% vs 4.1%
IBRT with DM 4 vs 6
1326 women
636 women Total
Age ≥ 65 y
Age ≥ 70 y 6 vs 32
ER+ ER+, 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%

Hughues KS et Al.. J Clin Oncol 2013; Kunkler IH et Al. Lancet Oncol 2015
OMISSION OF RT AFTER BCS
New studies based on molecular profile (ongoing)

- Luminal A, Ki-67 no >13%

LUMINA
- Age ≥60 years
Canada - Stage I, pN0, IDC, G1-G2, no EIC & LVI

- Low Oncotype-DX, RS (≤18)

IDEA
- Age 50-69 years
USA - Stage I, pN0

- Low Risk PAM50 score

PRECISION
- Age 50-75 years
Boston - Stage I, pN0, G1-G2

Omission of RT can be considered for older patients and favourable molecular profile
DCIS. WBI AFTER BCS

Author’s Conclusion. Implication for practice

Results confirms the benefit of RT after BCS

and support its use for all women

as the overall benefit was large

and all subgroups analysed

showed benefit for the use of RT

Goodwin A et Al. The Cochrane Collaboration, 2013; Lazzeroni M et Al. Cancer Treat Rev 2017
Locally advanced

breast cancer
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2014
NCIC-CTG-M20 TRIAL

5-year results WBI WBI + P value

RNI
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

1-3 N+ or ≥ 4N+
Lumpectomy
≥ 10 nodes dissected
≥ 1 of the following (with HR N-): G3, ER-, LVI+
Whelan TJ et Al. N Engl J Med 2015
EORTC TRIAL 22922/10925

No IMC-SC RT versus IMC-SC RT

Poortmans P et Al. N Engl J Med 2015
PMRT AFTER MASTECTOMY

PMRT in patients with pT3 and/or ≥4 N+

RNI in N1 cancers and adverse biological features (≤ 40 years, ER-, G3, extensive LVI)
Consider omitting PMRT in women with pT1-pT2, pN1 (1-3), and favourable biological profile
Consider omitting RNI in N1 (1-3 N+) in the absence of adverse biological profile
 RT AND NEOADJUVANT CHEMOTHERAPY

• Neoadjuvant chemotherapy
(NACT) does not improve
survival
• However, patients younger than
50 years should be considered
(possible survival advantage)
• pCR is the most important
prognostic factor
• PMRT ± RNI indications should
be based on maximal pre-
treatment staging
• Concurrent neoadjuvant RT-CT
could improve pCR and survival
Mamounas EP et Al. J Clin Oncol 2012; Botteri E et Al. Br it J Surg 2017; Gillon P et Al. Eur J Cancer 2017; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2018
PMRT AND NACT. PROGNOSTIC FACTORS

NSABBP B-18 & B-27

Tumor size
>5 vs ≤5 cm EORTC 10994/BIG 1-100
P=0.0095 Molecular subtype
Lum A vs no-Lum A
Nodal/breast p-stage P<0.0001
ypN-/pCR- vs ypN-/pCR+
ypN+ vs ypN-/pCR+ p-CR+ vs pCR-
P<0.001 P<0.0001

Mamounas EP et Al. J Clin Oncol 2012; Gillon P et Al. Eur J Cancer 2017
 TRIALS RNI AFTER NACT (ONGOING)

Study Design Primary End Point

NSABP B51 RNI vs no treatment in IBC-RFI
2013-…. pCR after NAC
ALLIANCE RNI vs ALND in IBC-RFI
A011202 persistent N+ after
2015-…. NAC
MA-39 RNI vs no RNI in low- ND in DFS
2015-…. risk disease
(biomarkers)
LYMPHEDEMA

Type of axillary surgery

Number of LN removed

Regional Node Irradiation

Lack of breast reconstruction

Adjuvant and neoadjuvant CT

Body Mass Index (BMI)

Chronic pain, functional impairment,
psychological distress, poor QoL Subclinical edema

Cellulitis

Overall Incidence: 21.4%; reported data in literature: <5% to >50%

DiSipio T et Al. Lancet Oncology 2013
LYMPHEDEMA
Standard RT Modified RT

Level I-IV and Rotter’s Node

IMRT Proton Therapy

Sparing lateral border of the SC field

LN draining the arm

Chandra RA et Al. Int J Radiat Oncolo Biol Phys 2015; Wang W et Al. Radiother Oncol 2018 (ARM Node)
TRIALS RNI IN N+ PATIENTS (ONGOING)

Study Design
POSNOC To investigate whether omitting adjuvant axillary
2014-…. treatment is non-inferior to ALND or RNI in ≤T2, N+
(1 to 2 macromets)
1900 patients, BCS or mastectomy
BOOG 2013-07 To investigate whether completion axillary treatment
2014-…. is non-inferior to axillary treatment (ALND or RNI) in
≤T2, up to 3 N+ (micro/macro)
878 patients, mastectomy
AMAROS TRIAL

1425 patients with N+, 744 ALND and 681 ART

Intention to treatment study (85% received treatment)
Median follow-up 6.1 years

Significantly less rate

Axillary relapse:
of lymphedema at 5-y:
- 0.54% (4 patients) in the surgery group 13.6% versus 28.0%
- 1.03% (7 patients) in the RT group
- No differences in OS and DFS

Axillary RT versus Axillary Dissection

Donker M et Al. Lancet Oncol 2014
OTOASOR TRIAL

2106 patients with N+, 1054 ALND and 1052 ART

Any clinical sign of toxicity at 1-y:
4.7% versus 15.3%
Axillary relapse:

- 2.0% in the surgery group

- 1.7% in the RT group
- No difference in OS and DFS

Axillary RT versus Axillary Dissection

Savolt A et Al. Eur J Surg Oncol 2017

 RT and
Reconstructive

Surgery
RT AND BREAST RECONSTRUCTION

Factors to be considered:
Breast reconstruction
14.8% in 2000
• General status, co- 31.9% in 2011
morbities, life-style, breast
size and shape, preference
• Stage of disease,
• Concomitant adjuvant
treatments
• Type of surgery
• Type of reconstruction
• Type of RT
Berbers J et Al. Eur J Cancer 2014; Fraiser LL et Al. JAMA Oncol 2018
PMRT
24.7% in 2000
30.0% in 2011
 RECONSTRUCTED BREAST. GEOMETRICAL DIFFICULTIES

Bad symmetry

Good symmetry

Fair symmetry
TIMING OF RT AND RECONTRUCTION

Total complication and

revision surgery rates
significantly higher for
implant reconstruction

after RT
(48.7%; range 38.8 - 58,6%),

than before
Berbers J et Al. Eur J Cancer 2014
(19.6%; range 0.9 – 38.3%)
TIMING OF RT AND RECONTRUCTION

Total complication and

revision surgery rates
significantly higher for
implant reconstruction

after RT
(48.7%; range 38.8 - 58,6%),

than before
Berbers J et Al. Eur J Cancer 2014
(19.6%; range 0.9 – 38.3%)
ONCOPLASTIC SURGERY. PLANNING THE BOOST

Scar based Clinical based By clips

CT based Composed
LOCALIZATION OF THE TUMOR BED
Radiation practice patterns among US ROs

33.1%: collaborating surgeon routinely

plase clips at the lumpectomy cavity

38.3%: clips occasionally placed

28.6%: clips not routinely placed

38.7% delivers a boost for patients with

OBS only if clips have been placed

34.6% uses boost regardless

of clip placement
Thomas K et Al. Pract Radiat Oncol 2014; Ward RC et Al. Breast J 2018
 RT in

Palliative Setting
STEREOTACTIC BODY RT (SBRT)
 CURRENT CHALLENGE

Radiation can potentiate the immunotherapeutic effect

by causing “immunogenic cell death (ICD)”, and
facilitate release and cross-presentation of tumour neo-
antigens, activation and priming of CTLs (cytoxic T-
cell), and increased infiltration of CD8+ CTLs in the
tumour microenviroment

When combined with immune checkpoint blockade,

radiation is best harnessed by hypofractionated
regimes (8Gyx3, or 6Gyx5), ideally in patients with
limited size lesions and relatively low disease burden
Vanpouille-Box C et Al, Clin Cancer Res 2017
CHECKPOINT BLOCKADE AND RT. ONGOING TRIALS

Immunoradiotherapy in
BC remains an under-
studied domain

Investigations that
delucidate the baseline
tumor profile and the
response to different
immunotherapy strategies
can provide indications
for including RT
to enhance the IT effect

Berbers J et Al. Eur J Cancer 2014

Hu ZI et Al, Int J Radiat Oncol Biol Phys 2017; Ye JC et Al, The Breast
 TAKE-HOME MESSAGE (I)

• The number of breast cancer will increase and

more cases are expected for RT in 2020-2025.
More tailored RT is needed in the era of
personalised medicine, with great attention to
QoL

• WBI remains a standard for most early stages

breast cancer. de-intensification in dose and
volume (PBI) can be considered for low-risk
groups. Omission of RT can be proposed in
older age patients
 TAKE-HOME MESSAGE (II)

• New techniques has shown to improve dose

homogeneity and reduce the dose to the
OARs. Versatility and flexibility are requested
to face the new challenges in HFRT, and
extended LR treatment (RNI)

• PMRT is the standard in high-risk groups,

indipendently from the type of surgery
(reconstructed breast) and response to NAC

• RT can play a big role in palliative setting

Thank you
very much
for your
attention
!!!!