Imaging for early stage breast cancer

IMAGING FOR EARLY STAGE BREAST CANCER

DR CARINE VAN DE MERCKT RADIOLOGY – BORDET INSTITUTE - BELGIUM

Thanks to Veronica Mendez

and Anne-Sophie Cardinael

IMAGING TECHNIQUES FOR EARLY BREAST CANCER DETECTION

• Mammography (digital, tomosynthesis) • Ultrasound • Breast MRI • Contrast-Enhanced Spectral Mammography (CESM)

EARLY DETECTION BREAST CANCER

42% breast cancer diagnosis : subclinical

25% DCIS

Normal Epithelial

Epithelial

DCIS Invasive

breast duct

hyperplasia hyperplasia

carcinoma

atypia

90 % microcalcifications

EARLY DETECTION BREAST CANCER : X-RAY

33% DCIS micro-invasive pattern

→

→

→

→

DCIS Non visible

DCIS visible (calcified)

Invasif non visible

Invasif visible

Invasif clinical

Preclinical stage = sojourn time 33 months

microcalcifications

Opacity disruption

EARLY DETECTION BREAST CANCER : MAMMOGRAPHY

→ microcalcifications

EARLY DETECTION BREAST CANCER : MAMMOGRAPHY

→ Architectural distorsion and opacity

EARLY DETECTION BREAST CANCER : MAMMOGRAPHY LIMITS

• Superposition of breast tissue • False image • Lesions seen on one view • Subtle images of distorsion • Overall sensibility (dense breast)

EARLY DETECTION BREAST CANCER : MAMMOGRAPHY LIMITS

- Dense breast (BIRADS 4) sensibility Rx : 55% - 40% of dense breast (3,4) in occidental population * (density majority genetically determined)

BIRADS 1 BIRADS 2 BIRADS 3 BIRADS 4

SENSIBILITY

Breast cancer risk

* Giger, AJR 2016

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : TOMOSYNTHESIS

Principles s

Aid of tomosynthesis → to avoid breast tissue overlapping

•9 exposures • 25°

Reconstructions in tomographic views Plan // detector

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE TOMOSYNTHESIS

Aid of tomosynthesis → to improve detection of architectural distorsion (BIRADS II, III >)

EARLY DETECTION BREAST CANCER : HOW TO I MPROVE THE SCREENING : TOMOSYNTHESIS Full digital standard Tomosynthesis

DCIS

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : TOMOSYNTHESIS

Ductal invasive

Standard 2015 Standard 2016 Tomo 2016

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : TOMOSYNTHESIS

Lobular invasive

Standard 2009 Standard 2016 Tomo 2016

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : TOMOSYNTHESIS

Cancer detection rate/1000 screening test European countries

Country

2D

2D + 3D

Multiplication rate

Norway

7,1

9,4

1,31

Italy

5,3

8,1

1,51

Sweden

6,3

8,9

1,41

+ 1 saved life / 2000 screening patients + 4 % mortality reduction

Radiology March 2015 : 274/3 : 772-780, LEE

EARLY DETECTION BREAST CANCER : TOMOSYNTHESIS LIMITS

• Microcalcifications analysis (look more benign) • Not proved better breast cancer staging

2D X-Ray

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : BREAST ULTRASOUND

Dense breast → BIRADS 1 → 98 % sensibility BIRADS 4 → 55 % sensibility

Rizzato, Eur Radiol (2001) – 11 : 2425-35

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE SCREENING : BREAST ULTRASOUND

US = 32% subclinical breast cancer only with ultrasound = more invasive tumor (< overdiagnosis)

Rx : 6 cancers/1000 women screened US : + 3 cancers/1000 women screened (invasive)

AJR 2003, Jun, 180(6) : 1670- 5 Leconte

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Imaging techniques with contrast injection are more accurate as non contrast techniques → MRI → CESM (Contrast-Enhanced Spectral Mammography)

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Breast MRI - Screening : high risk women of breast cancer

- Discordance between MG and ultrasound - Discordance between conventional imaging and clinical examination - Staging lobular carcinoma ? DCIS ? Ductal carcinoma

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Breast MRI – DCIS 16-47 % DCIS non calcified

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Breast MRI – DCIS

DCIS LOW GRADE

DCIS HIGH GRADE

MRI  RX 

37%

48%

MRI  RX 

13%

2%

• 83% false  = low grade DCIS

• Detection of intraductal extension RX : 48,4% US : 34,2% MRI : 68%

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Breast MRI – DCIS → Surestimation tumor size (17-38%) > low grade (benign associated lesion : HEA)

Normal Epithelial

Epithelial

DCIS

breast duct

hyperplasia hyperplasia atypia

→ Underestimation tumor size (11-38 %) (50% DCIS non visible MG + MRI) 9 – 15% DCIS autopsy : same clinical issue ?

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

BREAST MRI – DCIS - Conservative treatment + radiotherapy = 15% recurrence 10 years - Half invasive (invaded margins) - Resurgical rate for invaded margins : 30 % to 70 %

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

BREAST MRI → to decide specific treatment - Conservative treatment - Accelerated partial breast irradiation (APBI) - Neo-adjuvant chemotherapy

Mammography

Ultrasound

MRI

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

Accuracy of breast MRI staging • Mean additional rate of lesions MRI > MG + US • 20-30% homolateral • 4-6 % contralateral 35% DCIS 65 % invasive cancer (Increased risk lobular carcinoma or genetic tumor) • Change of treatment strategy with MRI : 28% survival impact ?

Sardanelli, Breast 2010, Liberman AJR 2003, Lehman NEJM 2007, Mann RM. Breast Cancer Res Treat 2008, Sardanelli F. Radiology 2007 Surg Oncol 2018 Mar; 27 - Paudel

EARLY DETECTION BREAST CANCER : HOW TO IMPROVE THE STAGING

BREAST MRI → additionnal lesion (ACR 3,4,5)

US second look



 ACR 3 : 20% malignity Microbiopsy + clip MR guided breast biopsy

Breast MRI : staging

53 yo DCIS 15 mm MG MRI: 7 cm lesion Surgery : multifocal

DCIS > 8 cm Mastectomy

ALTERNATIVE TO MRI : CONTRAST MAMMOGRAPHY (CESM) : MG + Iodine contrast injection

High energy

Low energy

Algorithm recombination

Morphological Analysis

Functionnal analysis //MRI

ALTERNATIVE TO MRI : CONTRAST MAMMOGRAPHY (CESM)

Malignant contrast enhancement optimal between 1 to 8 minutes

2 8

CC normal

CC patho

MLO patho

MLO normal

P/agrandi si néc.

ALTERNATIVE TO MRI : CONTRAST MAMMOGRAPHY (CESM) - No time consuming : 10’ - US second look in the same time

CESM VERSUS MRI : STAGING

Se homolateral

Se contralateral

False +

VPP

MRI

96%

88%

13%

85%

CESM

96%

56%

2%

97%

CESM → same sensitivity (MRI) homolateral → less sensitivity (MRI) contralateral

→ less dependent on cycle (non density dependent)

ALTERNATIVE TO MRI IN CASE OF :

- Pace maker - Claustrophobia

Advantages : - Faster examination (10’) - Fessible immediately after CESM → US second look - Less expensive - Better accessibility

Disadvantages : - non CESM guided biopsy

IRRADIATION ?

CESM → 2.99 mGy

3D tomosynthèse → 2.23 mGy

2D FFDM → 1.74 mGy

Literature : +6% (Fallenberg 2014)

+20% (Dromain 2012)

+81% (Jeukens 2014)

→ Doses inferior european threshold

CONCLUSION

Early breast cancer detection : → MG +/- ultrasound (dense breast) → tomosynthesis increase cancer detection → MRI (high risk patient)

Early breast cancer staging before APBI : → MRI (US second look – MRI guided biopsy) → CESM (US second look)

Pathology with an emphasis on early breast cancer

Dr. Denis Larsimont Pathologist Institut Jules Bordet

ESTRO school, Brussels, November 2018

Pathologist Role

• Try to estimate risk of local recurrence – margins • Try to estimate risk of distant recurrence – Pronostic and predictive parameters • (neo) Adjuvant treatment

Margins Evaluation

Margins/locale reccurence

Photo marge micro

• DCIS: margin ≥ 2mm (JCO 2016) • Invasive: no ink on tumor (JCO 2014)

Margins

• Bad News • Margins estimation is not an exact science

resident n°1 resident n°2

resident n°3 senior pathologist

?

Margins/Limitations

• Technical & methodologic – Pancake phenomenon – Specimen orientation – Problem with ink – Not uniform sampling method • Definition & interpretation

Schnitt SJ

Boston Breast Symposium 2018

Ink diffusion problem

Margins

• Margin evaluation: probabilities not absolutes. • Patients with positive margins: more likely to have residual disease at or near the primary site than those with negative margins. • But – A positive margin does guarantee residual disease. – A negative margin does not preclude extensive residual disease.

Schnitt SJ

Boston Breast Symposium 2018

Lumpectomy-Margins/Goals

• To identify patients more likely to have large residual tumor burden and require futher surgery. • To identify patients unlikely to have large residual tumor burden and do not require futher surgery

Schnitt SJ

Boston Breast Symposium 2018

Breast Cancer

• Important Pathological Parameters – Histological Type (NST, Lobular,…) – Size – Histological Grade

– Axillary Lymph Node Status – Lympho-vascular Invasion

– Hormonal Receptors (ER, PR). – HER2 status

– Response to neo-adjuvant treatment (RCB score)

Stage TNM

Stadz Stage

M etastasis

Mayo Clinic

Lymph N ode

T umor Margins

Margins

MofifieNCA

San Antonio Data Base

Gross Examination/Tumor Size

???

No Special Type (ductal)

Lobular

Histological Subtype

• About 90%

Prognosis variable

Others

Lobular

NST (former ductal)

Good Prognosis

Mucinous

Tubular

Poor Prognosis

Micropapillary

Lymphovascular invasion

• 2760 breast cancer LN - • 990 untreated / 1765 sélective treatment • FU: 13 years 6.8 years • Vascular Invasion: 19% – bigger size tumor – high histological grade – young age Lee et al. 2006 Eur J Cancer

Histological Grade

Scarff-Bloom-Richardson Score modified by Elston & Ellis

Tubule formation Majority of tumour Moderate degree

(>75%) - 1 point (10-75%) - 2 points (<10%) - 3 points

Little or none

Nuclear pleomorphism* Small, regular uniform cells - 1 point Moderate increase in size and variability - 2 points Marked variation - 3 points * Reference point - normal epithelial cells Mitotic counts - 1 - 3 points Dependent on microscope field area

Elston&Ellis Histopathology 1991

Nottingham Tenovus Primary Breast Cancer Study Histological Grade

1

.8

Grade 1

Cum. Survival

.6

Grade 2 Grade 3

.4

.2

246.723 2 <.0001 Chi-Square DF P-Value

0

0

4

8

12

16

20

24

0 712

342 403 414

76 82 96

Grade 1 Grade 2 Grade 3

48

96

144

192

240

288

1289 1717

Time

PROLIFERATION

MAI

Baak JP et al. JCO 2005

Proliferation/Ki67

- Pronostic - Predictive in neoadjuvant chemo - To distinct Luninal A vs B - Help to choose chemo. In ER+ BC (20% cut off).

BUT… Lack of reproducibility in the grey zone (10-30%)

Ki67

Post-Neoadjuvant Treatment

Molecular classification

ER-

ER+

PNAS vol 98, no 19, 10869-10874, 2001

Clinical evolution

New paradigm: Treatment on tumor biology and not only on tumor stage

Target Therapy

ER

HER2

Negative Predictive Value 95%

Immunohistochimie:RO/  E Score 0: no response

Positive Predictive Value 30-50%

Score 2-3: 20% probability of response

Score 4-6: 50% probability of response

Score 7-8: 75% probability de response

Allred Score

Leake J Clin Pathol 2000

Treatment

Decision Making

HER2 therapy

ER+

ER-

ER-

ER+

HER2 +

HER2 -

HER2 +

HER2 -

Endocrine Therapy Chemotherapy

Chemotherapy

ER+ tumors: luminal A vs B

Luminal B High risk Ki67 >

PROLIFERATION

Luminal A Low risk Ki67 <

→ Luminal ER+ HER2- BC is a spectrum !

Wiripati et al. Breast Cancer Res 2008

ER+ Luminal A versus B?

ER+ Breast Cancer is a spectrum

ER+ Ki67 Low

ER+ Ki67 High

<=10%

> 20%

Ki67 Threshold?

14% 20%

Tumor Infiltrating Lymphocytes/TILs

Prognostic Factor

Loi S et al. JCO 2013 Adams S et al JCO 2014 Wang K et al Oncotarget 2016 Denckert C et al Lancet Oncol 2018

TIL

Tumor cells

Predicitve Factor

Denckert C et al JCO 2010 Denckert C et al JCO 2015 Wang K et al Oncotarget 2016

Molecular tools

« GenomicSignatures » expressed In the tumor (microarray /NGS technology)

Microscope

Evolution of technologies to analyse Breast tumors

Tumor Grade: Genomic Grade Index (GGI) - Rationale

Starting point: histologic grade

van de Vijver et al. NEJM 2002 validation series Central Pathology Review

Grade 1

Grade 3

Grade 1 Grade 2

Grade 3

GG3

GG1

Grade 1 Grade 3

Genomic

Grade index

97 discriminating genes in ER+ (91% proliferation related)

Genome-wide Affymetrix™ microarray

35

Sotiriou et al, JNCI 2006

Courtesy C. Sotiriou

Prognostic value of genomic grade

All*- HG

HG2 subset

All*- GG

*Validation set - ER+ population

36

Sotiriou et al, JNCI 2006

Gene expression signatures

Cardoso F et al. N Engl J Med 2016; 375:717-729

• Level of evidence 1A for clinical utility of MammaPrint® in the clinical – high group • C-High/g-Low (48% N+ !) show a 5-yr DMFS >94% (with or without CT)

• In the whole population: 14% reduction in CT prescription • In the c-High subgroup: 46% reduction in CT prescription

Cardoso F et al. N Engl J Med 2016; 375:717-729

Use biomarker to treat

Genomic Signature invasion

Wound Signature

Tumoral size

Signature 70 gènes

Signature 76 gènes

Bad prognostic

Important Proliferation

Signature OncotypeDx

Lymph Node Status,

Molecular Classification

Genomic Grade

Biological characteristics of the tumor Proliferation = main characteristic

Stage of the tumor

Pathologist Today

Patho-morphologist

Patho-biologist

Surgeon

Oncologist

Biological Parameters

Pathological Parameters

-Hormonal Receptors

- Type

-Prolifération -HER2 (IHC,FISH) -Genomic signature -Mutational Profile

-Grade

-Margins

-Lympho-vascular Emboli

- TILs

-Liquid biopsy

Radiotherapist

Translational Research

Radiologist

Thank you

NEW BORDET

Ready in 2020

Former President

President

Philip Poortmans, MD, PhD

1

The basics behind the rise of APBI Background

Former President

President

Philip Poortmans, MD, PhD

2

I have no conflicts of interest

3

The basics behind the rise of APBI: background

Why not ?

Background: practical issue

Rate BCS

1.0

0.76

0.55

0.14

(42% RT)

Distance:

25

100

230

km 300

Athas WF et al JNCI 2000

Background: changing concepts in LR treatment

± 1970

± 2000

Maximal tolerable treatment

Minimal effective treatment

Background: local tumour spread

Holland R. Cancer 1985

Background: local tumour spread

 2cm -  4 cm

@ PA margin

@ 1 cm: 59-61%

@ 2 cm: 42-41%

@ 3 cm: 17-18%

@ 4 cm: 10-11%

5

0

10

15

Holland R. Cancer 1985

Background: recurrence pattern

Milan III

• N = 273

• Lumpectomy

• No RT • ● = recurrence or new tumour

Mannino M & Yarnold J. Radiother Oncol 2009

Background: patient wish…

Background: or marketing?

Background: real life…..

Many centers already use APBI on a regular basis

Background: guidelines

Background: target volume delineation

Background: target volume delineation

Target volume delineation of primary tumour bed:

- by dedicated RTO’s

- no clips

- no seroma

van Mourik AM et al. Radiother Oncol. 2010;94:286-91.

Background: target volume coverage

Bartelink H, et al. Radiother Oncol. 2012;104:139-42.

Background: target volume coverage

340 cGy

= tumour

= TE

= 4 cm line

Background: target volume coverage

1.0 cm

1.7 cm

= tumour

= TE

= 1 & 4 cm line

The basics behind the rise of APBI: background

Why (not) ?

The basics behind the rise of APBI: background

Poortmans P, et al. The Breast 2016; in press.

Background: role of RT

0 Gy

0 Gy

 50 Gy

 50 Gy

-15.4%

- 3.3%

5:1

EBCTCG Lancet 2011; 378: 1707–1716

Background: role of RT

0 Gy

0 Gy

 50 Gy

 50 Gy

-21.2%

- 8.5%

2.5:1

EBCTCG Lancet 2011; 378: 1707–1716

Background: role of RT

Dutch population based cancer registry

2000-2004 cohort: 37,207 patients

- 58.4% BCT

- 41.6% MRM

van Maaren M, et al. Lancet Oncol. 2016 Aug;17(8):1158-70.

Background: role of RT

Dutch population based cancer registry

2000-2004 cohort: 37,207 patients

- 58.4% BCT

- 41.6% MRM

van Maaren M, et al. Lancet Oncol. 2016 Aug;17(8):1158-70.

Background: stage migration

Percentages invasieve tumoren naar lokalisatie, stadium en incidentiejaar

C50, Borst

2003 2004 2005 2006 2007 2008 2009 % % % % % % % 38,6 37,7 39,4 39,8 41,9 41,2 41,8

Stadium*

1

41,3 41,5 41

40,1 40

40,4 39,5

2

14,7 14,8 13,8 14,2 12,8 12,2 12,7

3

4,5

5

5

5

4,3

5,1

4,9

4

0,9

1

0,7

0,9

1,1

1,1

1

Onbekend

100

100

100

100

100

100

100

Totaal

* Postchirurgische TNM (pTNM) aangevuld met de klinische TNM (cTNM)

Background: Interaction S and LR treatments

1/1.5

1/4

1/2-3

1/4

1/ 

Poortmans P. Lancet. 2014 Jun 21;383(9935):2104-6.

Background: open questions

• Patient selection criteria

• Optimal techniques

• Optimal schedules

• Volume definition (QA !)

• Long term FU:

– local control

– long term toxicity

Background: possible approaches

• Follow up is to short

• Definition risk groups

• Practical issues

• Doesn ’ t fit me: volumes, techniques; collaboration; …

Background: possible approaches

• Discuss in multidisciplinary team

• At least consider starting with low risk group

Background: possible approaches

• Level of evidence increases

• Longer follow up data

• Risk groups are defined

• Logistical benefits

• Most trials are closed

31

Radiation therapy: ever more focused!

C. Philippson Institut Jules Bordet, Brussels, Belgium

ESTRO teaching course on APBI, Brussels, Belgium, 11-14 November 2018

Introduction

• In 2015:

• 67.087 new diagnoses of cancer were registered (excluding non-melanoma skin cancer).

The disease affects approximately one in three men one in four women

before they reach the age of 75.

https://kankerregister.org

Introduction

https://kankerregister.org

Introduction

6,2%

11%

34%

42,5%

https://kankerregister.org

Introduction

https://kankerregister.org

Introduction

Presentation plan

• Evolution of breast cancer treatment • Understand how we came to APBI • Describe the different existing APBI techniques • Institute Bordet experience with IOERT

Introduction

Same goal

• Cure more and more patients

Different techniques • Local treatment • Systemic therapy

Introduction

Local treatments • Surgery • Radiotherapy

↗ Local control

Systemic treatments • Chemotherapy

• Hormonal treatment • Targeted therapy

↗ Survival

Introduction

➢ 42,000 patients ➢ 78 trials

 20% LR @ 5y :  5% Mortality @ 15y

EBCTCG, Lancet, 366-déc 2005; 366:2087-2106

Introduction ➢ N0

➢ N+

EBCTCG, Lancet, 366-déc 2005; 366:2087-2106

Introduction

Local treatments • Surgery

• Less mutilation

↗ Local control

• Radiotherapy

• Preservation of OAR

Systemic treatments • Chemotherapy

↗ Survival

• Hormonal treatment • Targeted therapy • Biological criteria

 20% LR @ 5y :  5% Mortality @ 15y

EBCTCG, Lancet, 366-déc 2005; 366:2087-2106

History

Internal mammary resection. J.URBAN (NY) M.MARGOTTINI (Italy)

Radical mastectomy. W.HALSTED (USA) B.PEYRILHE (France)

Modified mastectomy. D.PATEY (UK)

Modified mastectomy. J.MADDEN (USA)

1882 1924 1939 1948 1951 1965 1967

Lumpectomy. B.FISHER (USA) U.VERONESI (Italy)

Conservative surgery F.BACLESSE (France)

First conservative surgeries G.KEYNES (UK) V.PETERS (Canada)

History

20 year follow up confirm findings on conservative surgery

Results of lumpectomy B.FISHER

Hormonotherapy

1976 1981 1985 1994 2000 2020?

Chemo CMF (N+) U.VERONESI

Sentinel node biopsy. A.GIULIANO (USA)

Less # START

Results of lumpectomy. U. VERONESI

Less volume (A)PBI U.VERONESI

History

➢ 1986

DFS @ 8y

OS @ 8y

Radical Mastectomy

77%

83%

Lumpectomy Axillary dissection Radiotherapy

80%

85%

Veronesi, IJROBP,1986,12;5:717-720

➢ Radiation therapy can evoid mastectomy ➢ Same cure rate ➢ Less mutilation

Evolution of techniques

• Cobalt-60 and 2D dosimetry

➢ Clinical target volume defined by clinical examination

➢ Effective dose is deliverd to breast ➢ Not always homogeneous ➢ Potentially toxic doses at OAR

➢ skin ➢ lung ➢ heart

Evolution of techniques

➢ ’90s

➢ Clinical target volume defined by scanner ➢ Linac remplaces Cobalt-60 ➢ Beams are more energizing ➢ Skin protection ➢ Wedges and MLC ➢ Homogeneous dosis

Evolution of techniques

➢ 21st century

➢ 3D dosimetry ➢ More precision

➢ Less volume irradiated

Evolution of techniques

➢ 21st century

➢ IMRT & VMAT techniques

➢ Volume is segmented into innumerable small, elementary volumes ➢ Each small volume is treated by a large number of small beam whose intensity and direction are optimized to obtain the best dose distribution in the patient

➢ Excellent correlation between treated volume and prescribed dose

Evolution of techniques

➢ 21st century

➢ IMRT & VMAT techniques (+/- gating) ➢ Importance of selection criteria ➢ This technique could diffuses low doses in the patient (if the arcs treatment were not appropriate)

Quality treatment

➢ Linac:

➢ Integrated imaging (2D)

➢ Precision of patient positioning ➢ Real-time verification of positioning

Quality treatment

➢ Linac:

➢ Integrated imaging CBCT (3D)

➢ Real-time verification of patient positioning ➢ Real-time verification internal organ movements

Tailored radiotherapy

➢ Precision

➢ Reduce of safety margin ➢ Increase of dose per fraction ➢ Reduce the number of fractions ➢ Reduce the treated volume

Lumpectomy + (A)WBI

Older patients , smaller tumor size, lower grade, larger margins

Less treatment

What about less fractions?

➢ Breast cancer cells: more sensitive to shorts bursts of intense radiation than to small doses fractionated over several weeks

➢ Numerous studies: higher radiation doses over shorter treatments periods

➢ Assess the risk of recurrence/ toxicity

Less fractions

• It’s not new!

Sanz et al, BioMed Research International, 2018, art ID8321871

Less fractions

• It’s not new!

Sanz et al, BioMed Research International, 2018, art ID8321871

Less fractions

Less fractions

➢ more popular in clinical routine:

• START A : 17 centers (2.236 patients) – 41.6 Gy / 3,2 Gy day /13 # – 39 Gy / 3 Gy day/13 #

Same length treatment

• START B : 23 centers (2.215 patients) – 40 Gy / 2,67 Gy day/15 #

Shorter treatment

Less fractions

START A

START B

Lancet Oncol 2013; 14: 1086-94

same toxicity rates

Lancet Oncol 2013; 14: 1086-94

Less fractions

42,5 Gy (2,65 Gy 13#, 22 d)

N0

42,5 Gy (2,65 Gy 13#, 22 d)

Less fractions

➢ Hypofractionation is equal in terms of

➢ efficacy ➢ acute and chronic toxicities ➢ cosmetic results

Less volume

(A)WBRT

➢

At-risk portion of the breast

APBI

PBI 1# PTV=CTV

Around 20,000 patients were treated in phase III clinical trials!

APBI techniques

Techniques

➢ Non-invasive

➢ 3D External radiotherapy

➢ Photons/ electrons: 10 #, 2/d, 5 d ➢ IMRT (Intensity Modulated Radiation Therapy) ➢ photons: same fractionation but better conformation

✓ Avantages: ▪

knowledge of final AP results

▪ techniques available in all radiotherapy centers

✓ Disadvantages: ▪

healthy organs irradiated at low doses ▪ difficulties in targeting the tumor bed ▪ risk of hot spots

APBI techniques

Techniques

➢ Invasive

➢ Brachytherapy

➢ rigid or semi-rigid guides : 192 Ir HDR 34Gy, 10 #, 2/j : 5 d

APBI techniques

Techniques

➢ Invasive

➢ Brachytherapy

➢ With a balloon (MammoSite): 192 Ir HDR 34 GY, 10 #, 2/d : 5 d

! Only 20-25% of patients after lumpectomy can be treated with the mammoSite technique

Pawlik et al. Cancer 2004 ; 100:490-8

APBI techniques

Techniques

20 Gy at applicator surface 10 Gy @ 5 mm 5 Gy @ 10 mm

➢ Invasive

➢ Peroperative

➢ photons de 50 KV (40’)

➢ few mm tissues treated, dose rapid fall off

Intrabeam

Raggi X

APBI techniques

Techniques

➢ Invasive

➢ Peroperative

➢ Electrons de 4 to 12 MeV (in 2’)

➢ Irradiation of a large volume (10 à 40 mm)

Novac7, Hitesys

Mobetron, Intraop

APBI techniques

Techniques

➢ Invasive:

➢ Technique dependent dose homogeneity

Strahlenther Onkol 2006;182(6):342-8

APBI techniques

Techniques

➢ Invasive by electrons

– Advantages

• High ballistic precision • High dose in a single fraction in more sensitive oxygenated cells • Dose homogeneity • Healthy organs perfectly protected • Less side effects

– Disavantages

• Ignorance of the final pathological results • Technique not available in all radiotherapy centers

IOERT at Bordet

➢ Historical background (late 80’s)

Technical Considerations IOERT at Bordet

➢ MOBETRON system

• Mobile linear accelerator self shielded and ‘light’ (1,2 T) • Operate with 9 instead of 3 GHz • Accelerated electrons beam of 4, 6, 9 and 12 MeV • Dose rate: 10 Gy/min

• Aluminum applicators of 3 to 10 cm diameter • 3 tips: flat or beveled (15° and 30°) • boluses of 5 or 10 mm for every applicator

IOERT at Bordet

Criteria inclusion

– More than 40 years old – Ductal invasive carcinoma (preoperative biopsy) – pT less than 20 mm (peroperative analysis) – Free margins (peroperative analysis) – Unicentric (MRI) – Unifocal (MRI) – All HR – All grade

– pN0 (peroperative analysis) – No EIC or LVI (preop biopsy)

Surgical technique

Surgical incision

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Lumpectomy

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Tumour resection till the muscle

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Detachment of the gland

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Shield positioning on the muscle

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Shield positioning on the muscle

Surgical technique Surgical technique

Suture of the tumour bed

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique Surgical technique

Applicator positioning

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Surgical technique

Soft docking

Surgical technique

Shield extraction, oncoplastic surgery

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Specific technique

– Margins

• 10 to 20 mm (except ant & post) • Peroperative analysis: margin

– Applicator diameter • 40 to 45 mm bigger than the tumour size (perop)

– Safety margin • Surgery + IOERT: at least 35-40 mm around the tumour bed

Specific technique-Target volume Specific technique

– Thoracic shield • Diameter: 10 to 15 mm bigger than the applicator (shield coverage) • Shield coverage perfect with our new system

– In vivo dosimetry • 3 LiF TLD

– Energy choice

• In function of the maximum target tissue thickness (measured with a needle)

Philippson C, Nogaret JM, EMC-Gynécologie, 2012; 7(4): 1-8

Thoracic shield & Dosimetry The presence of the shield will generate backscattered electrons and this gives a local overdosage. The range of BS electrons is roughly one cm and most of them are absorbed in the Aluminum layer

12 MeV Depth dose curve Monte Carlo Simulation, with and without the shield placed at the depth of the 90% isodose line With our composite shield, the local overdosage is limited to 10% and gives even a more homogeneous dose distribution. (also confirmed by physical measurements)

➢ Technical parameters/Radiation safety Dosimetry

Depth Dose curve 4, 6, 9 & 12 MeV dia 50 mm Depth Dose curve e dia 50 mm

Except for the 12 MeV, a bolus is often needed in order to have 90% at the beam entrance

Very limited braking radiation X-ray contamination is significantly lower in the Mobetron Beam ( 0,7 % vs 2 %)

In Vivo Dosimetry

580 low-risk patients selected for PBI with the Mobetron (Intraop) over a 5-year period

LiF-100 chips were used as detectors

1709 dose points recorded at 3 different sites (Thyroïd, contralateral Breast, Gonads)

N Min.

Max.

Mean St.

N Min.

Max.

Mean St.

N Min. Max. Mean St. Dev.

Dev.

Dev.

565 0.02 1.97

0.40

0.23

570 0.01 1.19

0.14

0.11

574 0.08 4.2 0.80 0.59

Jules Bordet Experience

– February 2010 till October 2018

– 1139 breast IOERT procedures

• 926 patients: exclusive treatment • 18 patients: exclusive bilateral treatment • 96 patients: boost treatment

– Dose 21 Gy on the 90% isodose

– Mobile linear accelerator self shielded: ● Mobetron (IntraOp)

– Follow-up: median 48 months

➢ Age & Stage

Age distribution

Age

40-49

50-60

>60

%

13

32

55

Stage

T

T1a

T1b

T1c

Total

% 4,1

38,8

57,1

100

Jules Bordet Experience Collimator size (dia in mm) distribution

65 mm 1.9%

35 mm 0.1%

40 mm 0.0%

45 mm 6.3%

60 mm 26.9%

50 mm 26.5%

55 mm 38.4%

Jules Bordet Experience ➢ Collimator distribu ion for pT1a, pT1b, pT1c

10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 %

pT1a

10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 %

pT1b

0.0 5.0

35 mm 40 mm 45 mm 50 mm 55 mm 60 mm 65 mm

0.0 5.0

35 mm 40 mm 45 mm 50 mm 55 mm 60 mm 65 mm

10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0 %

pT1c

0.0 5.0

35 mm 40 mm 45 mm 50 mm 55 mm 60 mm 65 mm

➢ Energy distribution

0%

4 MeV

12%

6 MeV

9 MeV

43%

12 MeV

45%

➢ Final AP

Pathology

AP Ductal

Lobular Mixed Mucinous Medullary Papillary

% 95,5

1,8

1

1,3

0,2

0,2

Nodes

Stage

pN0

pN1mic

pN1a

%

96,1

2,2

1,7

Grade

I

II

III

%

42

39

19

Jules Bordet Experience ➢ Histology: molecular subtypes

%

Luminal A

65

Luminal B

20

Triple negative

7

HER2/neu +

7

Unknown

1

Jules Bordet Experience ➢ Adjuvant treatments

HT \ CT (%)

YES

NO

Total

YES

15,5

74,1

89,6

NO

7,6

2,8

10,4

Total

23,1

76,9

100,0

➢

Toxicities

Acute toxicities GRADE 1 (%)

GRADE 2 (%) GRADE 3-4-5 (%)

Infection

0,1 0,8 1,2 0,2 0,0

0,4 0,2 0,8 0,1 0,6 2,1

- - - - - -

Heamatoma

Delayed Cicatrisation Local Inflammation

Delayed Cicatrisation+Inf.

2,3

Total

Acute toxicity according to NCI CTCAE v 3.0

Late toxicities GRADE 0 (%) GRADE 1 (%) GRADE 2 (%) GRADE 3-4 (%)

Fibrosis Atrophy

94,6 97,3

3,0 2,1 5,1

1,9 0,1 2,0

- - -

Lent Soma scales

Jules Bordet Experience

Cosmetic results

G0: no effects G1: minimal asymmetry or scar prominence G0: no effects G1: minimal asymmetry or scar prominence G2: asymmetry ≤ 1/3 of the gland G3: asymmetry > 1/3 of the gland G2: asymmetry ≤ 1/3 of the gland G3: asymmetry > 1/3 of the gland

2%

Very Good

11%

Good

Fair

28%

Bad

59%

J Results

– 23 local relapses ( 5 in-quadrant ) – 3 metastatic patients – 29 deaths – 4 due BC metastasis – 10 due to another cancer

– 15 without relation with cancer

Median FU: 48 months

Crude recurrence rate = 3 % Crude yearly recurrence rate = 0,75 % Recurrence rate after 48 months: 2,2 % DFS : 95,9 % OS at 48 months: 97,3 % Cancer SS: 98,2 % BC SS: 99,5 %

Results

Age s

Results

pT

pN s

Results Grade s

Results Her2/neu s

neg pos

Results Triple neg s

Results Histologic subtypes

Results ASTRO ESTRO

Conclusions • Importance of preoperative Work-Up • Importance of surgical procedure • IOERT PTV adapted to the pT • Acute and late toxicity rates very low • Maximal protection of normal tissues

No evident correlation between – Her2neu and local relapse – Grade 3 and local relapse – BRCA? – History of breast cancer? – Perop workup non optimal?

Conclusions Conclusions

– Gain in quality of life – Necessity of a multidisciplinary team – Importance concept of Local control & Survival with ratio 4:1 – ↘20% local recurrence at 5 y – ↘ 5% death rate at 15 y

– Median Follow-up still too short – Necessity of a significant initial investment

How does one decide which approach is best ?

➢ Standard WBI ➢ AWBI ➢ APBI • 3D/IMRT

• Brachytherapy • IORT

➢ No RT

➢ I hope this course will give you response(s) to this difficult question!

thank you for your attention

Target definition in partial breast irradiation GEC-ESTRO consensus V.Strnad

University Hospital Erlangen

3 pillars of APBI Target definition and delineation Key to success of APBI

3 pillars

Patient selection

Target definition

Appropriate technique

University Hospital Erlangen

GEC-ESTRO guidelines for target definition in breast brachytherapy

GUIDELINES

Target localization

Target definition

University Hospital Erlangen

GEC-ESTRO guidelines for target definition in breast brachytherapy

GUIDELINES

BACKGROUND

Target localization

Target definition

AVAILABLE INFORMATIONS

University Hospital Erlangen

GEC-ESTRO guidelines for target definition in breast brachytherapy

GUIDELINES

BACKGROUND

Target localization

Target definition

AVAILABLE INFORMATIONS

University Hospital Erlangen

Target definition and delineation

What we can use?

1. Scar - skin

2. Imaging (Ultrasound, Mammography, MRI, CT)

3. Surgical report

4. Surgical clips

5. Scar inside of breast

University Hospital Erlangen

Skin scar

Scar

Scar

x x

x

Clips

Clips

Scar

Clips

x

x

x

Clips

Sca

University Hospital Erlangen