Controversies in Radiation Therapy for Breast Cancer?

Prof. Yazid Belkacemi

Patients’ selection for APBI out of trial?

Patients’ selection for IORT?

Hypofractionation RT new standard in BC?

Controversies in Radiation Therapy for Breast Cancer?

Is there a subgroup of patients who may benefit equally from APBI or WBI?

Standard RT in Breast Cancer

Tumor bed

TechniquesIntra opIntra opproceduresprocedures

Intra or post op Intra or post op implantation implantation

Post op irradiationPost op irradiation

CASE 1CASE 1Ms. D. Ms. D. 54y of age 54y of ageMenopausal status confirmed since 50 y Menopausal status confirmed since 50 y No significant co morbidityNo significant co morbidityRegular mammograms since 10 years : no Regular mammograms since 10 years : no

abnormalitiesabnormalitiesSelf discovery of a 1 cm mass in the Upper Self discovery of a 1 cm mass in the Upper

Outer Quadrant of the right breastOuter Quadrant of the right breastMammogram and US: ACR5Mammogram and US: ACR5Biopsy: ductal ADK grade I, HR+Biopsy: ductal ADK grade I, HR+

CASE 1CASE 1Lumpectomy + SLNBLumpectomy + SLNBPathology report: Pathology report:

Ductal invasive carcinoma, size: 15 mmDuctal invasive carcinoma, size: 15 mmDCIS component 10%DCIS component 10%Grade I Grade I Minimal margins size 2mmMinimal margins size 2mmER+ PR-, HER2-, Ki67 5%ER+ PR-, HER2-, Ki67 5%No LVINo LVI2SN - 2SN -

Would you recommend APBI out of clinical trial ?

YES

NO

54 ypT1 11mmMargins 2mmER+ HER2-SN-

If this patient was 70yWould you recommend APBI out of

clinical trial ?

YES

NO

70 ypT1 11mmMargins 2mmER+ HER-SN-

APBI consensus statement from the ASTROAPBI consensus statement from the ASTRO― Based on 645 original research articlesBased on 645 original research articles― 4 published randomized clinical trials4 published randomized clinical trials― 38 published prospective single arm studies38 published prospective single arm studies

““Suitable” groupSuitable” group““Cautionary” groupCautionary” group““Unsuitable” groupUnsuitable” group

Sélection des patientesSélection des patientes

Smith BD et al. IJROBP, 2009

APBI consensus statement from the ASTROAPBI consensus statement from the ASTROASTRO consensus statement guidelines regarding patient selection for

accelerated partial breast irradiation off clinical trial

Smith BD et al. IJROBP, 2009

GEC - ESTROGEC - ESTRO

DIFFERENCESDIFFERENCES

3 bras

SHARE

2 bras2 bras2 bras2 bras2 bras

2800

> 50 et Ménop< 20

pN0 pN0(i+)I, II, III< 2mm

RTC 3D

40Gy/10f

Hypo 40Gy/3W 42.5Gy/3w50Gy/25+16 NON

3 bras

If this patient was 70yWould you recommend INTRAOP out

of clinical trial ?YES

NO

70 ypT1 11mmMargins 2mmER+ HER2-SN-

Novac-7Novac-7 4-12 MeV 4-12 MeV 20 Gy 20 Gy in 3-5 minin 3-5 min 650 kgs650 kgs(Hithesys)(Hithesys)

MobetronMobetron 4-12 MeV 4-12 MeV 20 Gy 20 Gy in 3-5 minin 3-5 min 1275 kgs1275 kgs(SRCLinac)(SRCLinac)

Intrabeam X-Ray 50kV Intrabeam X-Ray 50kV 5 Gy @ 1cm 5 Gy @ 1cm in 25-30 minin 25-30 min 1.8 kg1.8 kg 20 Gy @ surface20 Gy @ surface

0

20

40

60

80

100

120

0 20 40 60Depth (mm)

Rel

ativ

e d

ose

(%

)

INTRAOP techniquesINTRAOP techniques

DoseDose

Uniform spherical radiation fieldUniform spherical radiation field Steep dose gradientSteep dose gradient High dose rateHigh dose rate

Design Design (n = 2232, 9 countries – 28 (n = 2232, 9 countries – 28 centres)centres)

Randomisation 1.1 (pre ou per operative)Randomisation 1.1 (pre ou per operative) Patients criteriaPatients criteria Age 63 y , pT ≤ 3cm: 86 %, grade I/II: 84 %, N-: 83 %, HR+: Age 63 y , pT ≤ 3cm: 86 %, grade I/II: 84 %, N-: 83 %, HR+:

90%90%

TreatmentTreatmentTargit Arm : 86% received the planned RTTargit Arm : 86% received the planned RTWBI in 14%WBI in 14%

FUPFUP > 4 y n = 420> 4 y n = 420

Lancet 2010, 376, 91-102

The Lancet 2010

ToxicityToxicity IntrabeamIntrabeam WBIWBI SeromaSeroma 2.1%2.1% 0.8%0.8% Grade 3-4Grade 3-4 0.5%0.5% 2.1%2.1%Local Control at 4yLocal Control at 4y LR rate LR rate 1.20 %1.20 % 0.95%0.95% (p=0.41)(p=0.41)ConclusionConclusion

There is non inferiority with INTRABEAM compared to WRIThere is non inferiority with INTRABEAM compared to WRI

Lancet 2010, 376, 91-102

San Antonio 2012San Antonio 2012 UpdateUpdate

Whole populationWhole population n=3451 n=3451 INTRABEAM armINTRABEAM arm n=1721n=1721EBRT armEBRT arm n=1730n=1730Minimal FUP of 4yMinimal FUP of 4y n=1010 n=1010 Minimal FUP of 5yMinimal FUP of 5y n=610n=610

Since 2010 : local recurrence events increased from 13 Since 2010 : local recurrence events increased from 13 to 34to 34

Local recurrence probability at 5 y is in favour of EBRTLocal recurrence probability at 5 y is in favour of EBRTInferiority of INTRABEAMInferiority of INTRABEAM

INTRABEAM 23 (3.3%) vs EBRT 11 (1.3%), INTRABEAM 23 (3.3%) vs EBRT 11 (1.3%), p=0.042p=0.042

Vaidya J.S Vaidya J.S et al., et al., SABCS 2012, S4-2SABCS 2012, S4-2

ConclusionConclusion

No difference if PgR+

Suitable group for INTRABEAM

(> 60 y, HR+, tumor < 2 cm, SN-)

Vaidya J.S et al., SABCS 2012, S4-2

Is there anymore discussion for Hypofractionation RT in BC ?

CASE 2CASE 2 Ms A-R. Ms A-R. 50y of age50y of age Peri menopausal status Peri menopausal status No significant morbidityNo significant morbidity Large size breast (100 D)Large size breast (100 D) Lumpectomy + SNBLumpectomy + SNB

Ductal invasive carcinoma pT1 18 mm; margins: 3mm Ductal invasive carcinoma pT1 18 mm; margins: 3mm Grade III (3,2,3), No LVI, Ki 67: 25%Grade III (3,2,3), No LVI, Ki 67: 25% ER+ 40% PR+ 20% HER2- ER+ 40% PR+ 20% HER2- 2 SN : 1 micromets. 2 SN : 1 micromets. No secondary ALND No secondary ALND

Adjuvant CTAdjuvant CT 4FEC 100 and 2TXT. Neurotoxicity G34FEC 100 and 2TXT. Neurotoxicity G3

Radiotherapy modalityRadiotherapy modality

Would you recommend:

1. Hypofractionated schedule in 3 weeks

2. Standard in 6.5 weeks

50y peri menopausalpT1 18mmSN micrometastsis/2No secondary ALND

Radiotherapy modalityRadiotherapy modalityWould you recommend nodal irradiation ?

YES

NO

50y peri menopausalpT1 18mmSN micrometastsis/2No secondary ALND

HypofractionationCanadian trial

50Gy in 25 fractions - 5 wvs

42.5Gy in 16 fractions - 3 wStratification : age (50); T (< 2cm); adjuvant TRT & centre

0,1

0,08

0,06

0,04

0,02

0

6,2 %

Years since randomization0 2 4 6 8 10 12

6,7 %

Recu

rren

ce (%

)

1 3 5 7 9 11

612

622

578

592

550

548

499

500

470

447

410

406

218

214

597

609

592

569

553

524

485

472

449

430

317

330

SWBI

AHWBI

FUP : 144 m

Cancer Care Ontario Regional Cancer Centres; Princess Margaret Hospital; Montreal General Hospital

Whelan et al. NEJM 2010

Hypofractionation

Stratification by tumor size < 2cm

No boost, no nodal RT

No N+ patients included

No large breast

Small proportion of pts with CT

Better cosmetic results

Impact of age and T size

Canadian trialComments: the results could be extrapolated to all pts?

Whelan et al. NEJM 2010

50y peri menopausalpT1 18mmSN micrometastsis/2No secondary ALND

START TRIALS

TrialTrial PopulationPopulation FUPFUP(y)(y) TreatmentTreatment

Local Local recurrencerecurrence

(%)(%)

Start BStart B(n= 2215)(n= 2215)

T1-T2T1-T2N-N-R0R0

6640 Gy/15fr/40 Gy/15fr/

(2.67 Gy/fr) 19j(2.67 Gy/fr) 19j 22

50 Gy/25fr/35j50 Gy/25fr/35j 3.33.3

Start AStart A(n=2236)(n=2236)

T1-3T1-3N0-1N0-1M0M0BCS or total BCS or total mastectomymastectomy

5.15.1

41.6 Gy/13 Fr41.6 Gy/13 Fr(3.2 Gy/fr)(3.2 Gy/fr) 3.23.2

39 Gy/13 fr39 Gy/13 fr (3 Gy/fr)(3 Gy/fr) 4.64.6

50 Gy/25 fr/35j50 Gy/25 fr/35j 3.23.2

START TRIALS

Meta-analysis of START pilot & START A&BSubgroup analyses of LR relapse (n=5861)

better

.4

Hazard Ratio (95% CI)

Fraction sizes > 2.0 Gy Fraction size 2.0 Gybetter

AgeAge

Primary surgery

Axillary nodes (pN)

Tumour gradeTumour grade

Boost RT

Adjuvant CTAdjuvant CT

.6 .8 1 1.2 1.4 1.6 1.8 2

< 50 yrs< 50 yrs> 50 yrsBreast conservingMastectomy

NegativePositive

1233NoYes

NoYesYes

138944725348513

43181421

12132398127227493071

43461480

0.84 (0.62, 1.15)1.07 (0.83, 1.38)0.97 (0.80, 1.19)0.91 (0.46, 1.81)

1.10 (0.86, 1.40)0.80 (0.57, 1.11)

0.96 (0.51, 1.82)1.07 (0.72, 1.59)0.86 (0.59, 1.25)0.99 (0.74, 1.32)0.99 (0.76, 1.29)

1.09 (0.86, 1.38)0.81 (0.57, 1.14)

No of patients

Hazard ratio (95% CI)

Haviland JS et al., SABCS 2012, S4-1

50y peri menopausalpT1 18mm GIIISN microM/2, No ALNDCT+

Haviland JS et al., SABCS 2012, S4-1

Patients50y peri menopausalpT1 18mm GIIISN microM/2, No ALNDCT+

ThaThank you!nk you!