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 !!!!

roberto.orecchia@ieo.it

Looking in the molecular biology

we will try to give a real tailored

RT treatment

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