“Partial Breast Irradiation” PBI

Dr Vincent RemouchampsService de Radiothérapie Oncologique

Clinique Ste Elisabeth Namur

Belgian Breast Meeting 2010Brussels

Plan: Partial Breast Irradiation From “maximum tolerable” to “minimum efficient”• Principles et Objectives (theory)• Methods• Carefulness et Inconvenients• Studies• Conclusions:

– Consensus USA / Europ, other experts opinions• Disgression:interest for boost (+ WBRT)

Principle: accelerated RT on a smaller volume (tumor bed,...)

• Limited volume• Protection of healthy tissues• Larger doses• Reduction radiation time

– classical: 6.5 weeks (ou 3 weeks)– turns to 1 week or even 3 min …!– Enough to make the cover of “Le Soir” this

spring ...

Objectives• USA, Italy: Diminish the under-use of breast

conserving surgery or of the post op radiation (in Italy, 20-50% skip RT depending on distance…)

• Reduce the duration, the cost, the side effects and discomfort of post op radiation therapy

• Improve Quality Of Life• Suppress sequencing issues with chemotherapy• Potentially improve prognosis by reducing overall

treatment duration?

FA Vicini. J Clin Oncol 19:1993-2001, 2001. and KB Baglan. IJROBP

2001

Methods (1): Brachytherapy

• The longer follow up• 2 fractions per day, 5 days.

(10x 3.4 Gy)

• Current practice for boost• Consensus ESTRO 2010:

may be the only technique valid for recommandations

Methods (2): IOERT Intra Operative Electrons Radio Th

Methods (2): IOERT (electrons)• For exemple “Mobetron”

(Dutoit)• Adaptable depth• 21 Gy in 3 minutes• Lung protection• More dissection• ELIOT study in Milan

(ELectron IntraOp Ther.)• expensive: 2 second hand

machines in Belgium, 1 in UZA for boost only (validated)

Methods (3):Low energy X Rays (50 Kv)

• “Intrabeam” (Zeiss)• “TARGIT” A and B studies• More superficial: treat 7-10

mm, 20 Gy in +- 20 min• more “Round”

Methods (3): Low energy X Rays (50 Kv)

Methods (4): External Beam conformal Radiation Therapy

(EBRT)

38 Gy in 10 fractions of 3.8 Gy, 2 fractions /day (1 week)

With existing machines!

Methods (4): EBRTDose distribution

Transverse Sagittal Coronal

Biopsy Cavity

CTVPTV 100%

IDL

105% IDL

50% IDL

important volume : reported toxicities; new study in Holland

Methods (5): Balloon Catheter‘MammoSite’

• MammoSite device (Proxima Therapeutics)

• Inflatable Balloon Placed In Lumpectomy Cavity At Surgery

• Remote Afterloading• 34 Gy (3.4 Gy X 10) en 5

jours• Toxicity if close to skin• Conflicts of interest (not

me)

Arguments against Partial Breast Irradiation

…than (currently) supporting the classical whole breast irradiation after

breast conserving surgery

1) STANDARD = partial surgery followed by whole breast

Radiation Therapy• 2500 patients 20 years follow up, randomised

phase 3 studies

• Evidence Based MedecineLevel I

2) Veronesi et al, Ann Oncol. 2001;12(7):997-1003

RandomisedPatients

10 yearsIpsilateralrelapses

Quadrantectomy 299 23.5%

Quadrantectomy+ whole breastRadiotherapy

280 5.8%

2) Veronesi et al, Ann Oncol. 2001;12(7):997-1003

• Quadrantectomies by Véronesi were large.• Correspond to tumorectomy + quadrant

irradiation• We can anticipate that post op irradiation of

quadrant only will be insuffisant

3) What is the target volume?

• 85% of relapses in index quadrant. 15%??• Multifocality / Multicentricity exists (MRI

and pathology studies)• Published extensive clinical experience has

prouved most of these foci are controled by whole breast radiotherapy

Schmitz AC, van den Bosch MA, Loo CE, et al Radiother. Oncol. 2010 [Epub ahead of print]

Precise correlation between MRI and histopathology - Exploring treatment margins for

MRI-guided localized breast cancer therapy.

• 64 wide local excision specimens were subjected to detailed microscopic examination. The size of the invasive (index) tumor was compared with the MRI-GTV. Subclinical tumor foci were reconstructed at various distances to the MRI-GTV.

• Subclinical disease occurred in 52% and 25% of the specimens at distances of 10mm and of 20mm, respectively, from the MRI-GTV

• A 1 cm margin undertreats up to 52 %, a 2 cm margin undertreats 25%, depending on the surgical margin… (studies: 1-2 cm, RTOG 1.5 cm)

3) What is the target volume?

• ...• No correlation between tumor size cavity size...• 90-95% of tumors located at the edge of specimen (Stroom

IJROBP 2009)

• Van Mourik 2010: Large interobserver variability for target definition if no seroma ...

4) About cosmesis?(External beam APBI)

• Hepsel et al, IJROBP 2009: « remarkably high moderate to severe late normal tissue effect » – 25% moderate to severe fibrosis (8% grade 3)– 18% unsatisfactory cosmetic results

• Jagsi et al, IJROBP 2009:– 21% unsatisfactory cosmetic results

4) About cosmesis? (2)

• Skin sequelae after mamosite, intra-op, (seroma and ponctions more frequent, …)

• Brachytherapy: Poti IJROBP 2004:– > 59% grade III toxicity

(fibrosis, telangectasia, necrosis, …): pictures

– 50 % unsatisfactory cosmetic results

5) Median follow up too short!• 2/3 of relapses after

conserving surgery are late

• The 2 randomised studies have 2 and 6.8 years median follow up (too short!).

Veronesi, Nejm 2002

Exemple:

Different slopes: RT is preventing late relapses!!

META-ANALYSE: EBCTCG Lancet 2005; 366: 2087-2106

Long follow up is essential for adjuvant breast treatment...

BCS

BCS + RT

6) Final histology after RT …!

• If Intra-operative– electrons– X rays– brachy perop

• If + margins or discovery of multifocality:? Re-excision? Mastectomy conversion?

Context:• Tremendous pressure

– from patients (comfort)– from industry (sales)– from hospitals, surgeons (concurrency)

• 645 research articles, 4 published randomised studies, (+1 négative metanalysis), 38 single arm prospective studies

• 2009-2010 publication of recommendations

Single arm studies with suboptimal selection criteria and > 4 years f- up from Polgar et al, Rad Oncol 94(3) 264, 2010

Institution Technique MedianFup

Local Recur. %(n)

Annual LR(%)

Comments

Uzsoki Brachy 12 24 (17 of 70) 2 5 cm, unk MgChristie Electrons 8 20 (69 of 353) 2.5 4 cm, unk MgCookridge Electrons 8 12 (10 of 84) 1.5 4.5 cm, N+London Brachy 7.6 15 (6 of 39) 2 4.5 cm, ILCTufts Brachy 7 9 (3 of 33) 1.3 Close M, EICGuys I Brachy 6 37 (10 of 27) 6.2 4 cm, N+Guys II Brachy 6.3 18 (9 of 49) 2.9 4 cm, N+, +MgOsaka Brachy 4.3 5 (1 of 20) 1.2 15% +Mg, EICFlorence Brachy 4.2 6 (7 of 115) 1.4 5 cm, N+, ILC

ALL 4.2-12 17 (132 of 790) 1.2-6.2

Single arm studies with stringent selection criteria and > 4 years f- up from Polgar et al, Rad Oncol 94(3) 264, 2010

Institution Technique Median Fup Local Recur. %(n)

AnnualLR (%)

Budapest I Brachy 11.1 9 (4 of 45) 0.8WBH Brachy 9.7 5 (10 of 199) 0.52Orebro Brachy 7.2 6 (3 of 51) 0.83RTOG 9517 Brachy 7 6 (6 of99) 0.91Budapest II Brachy 6.8 4.7 (6 of 128) 0.69Oschner Brachy 6.3 2 (1 of 51) 0.32Ninewells Brachy 5.6 0 (0 of 11) 0German Brachy 5.3 3 (8 of 274) 0.55FDA Mammos. 5.2 0 (0 of 43) 0Kiel HNIO Mammos. 5 0 (0 of 11) 0Navarra Brachy 4.4 4 (1 of 26) 0.86Wisconsin Brachy/M. 4 3 (8 of 273) 0.72Kansas Brachy 4 0 (0 of 25) 0

ALL 4 – 11 years 3.8 (47 of 1236) 0-0.91

7 Main Randomised Phase III trials:PBI versus whole breast RT

Study Technique Accrual Remarks

Targit X raysPerop

2232 Lancet 2010 ; only 20 % ofpatients followed > 4 years,1.2 % and 0.95 % relapse,median FU short (2 years)

Eliot ElectronsPerop

1822 Announced SABCS 2010

HungarianPolgar6.8 y medianFollow up

Brachy (88)/electrons in25 fractions(40)

258 Int JCO 2009 ; Local relapseWBRT 3.3%, BT 5.1%, CI0.6-2.3 % ! ! ! , methodsdiscussed

RTOGNSABP

Brachy +others

Target9000 ?

5 year results in 5-10 years !

GEC ESTRO Brachy Target1100

Awaited

IMPORT,IRMA, …

Awaited

Local recurrence as a function of age in prospective APBI studies

AGE All studies Crude LR % (n)< 40 10.5 % (2 of 19)> 40 – 50 7.6 % (16 of 211)> 50 - 60 3.7 % (12 of 322)> 60 3.4 % (18 of 531)All age 4.4 % (48 of 1083)Follow up 5-9.7 years

Level 4 evidence (weak): expert recommandations for “suitable”

ASTRO 2009 (USA)• > 60 y.o., no BRCA• T < 2cm, unicentric,

unifocal, inf. ductal, no ILC, no pure DCIS

• Margins >2 mm• pN0, no LVI, no EIC• no neo-adj chemo/ht

ESTRO 2010 (Europ)• > 50 y.o.• T < 3cm

• same for the rest

Radioth Oncol, march 2010 Recommendations GEC-ESTRO

• Acceptable outside studies for very selected patients but ...

• “Gec Estro Accept no liability for …” !!!• “The validity of the statement may be limited to

multicatheter technique.”• “The 5 year results of the randomised trials …

will be available only in the next 5 to 10 years …”

Editorial with the American recommendations

• 5 years results of random studies available in 10 years (5 years = short for adjuvant breast!)

• “Suitable” are generally older, with less aggressive tumors

• “Whole breast RT remains the gold standard… longer track of records about efficacy and safety”

• Alternative fractionation (15-16 x) or even lumpectomy alone … better supported by data”

…and the most cost effective (Suh IJROBP 2009)

Even Orecchia admits, at the PRO-CONTRA session at Estro 2010

• 80-85 % not suitable for PBI• PBI is not standard• PBI is experimental• Late complications occurs (necrosis at

follow up mammograms)

Conclusion:Partial Breast Irradiation?

Modify the principles of breast conserving treatment?

• Better than nothing? Not in Belgium…!• ETHICS: security ??, efficacy ??, … than:• Wait for a sufficient follow up of phase III studies• Opinion of NHS: it is experimental• St Gallen: Is it still experimental ?

Panel vote (86 % yes; 14% no)

… and for the Boost?• Very attractive techniques

– Used for many years with brachy-therapy, if indicated (margins, treatment depth, …)

– Attracting developments in intra-op• SABCS 2009: Targit Boost n=300• 1.73% local recurrence at 5 years… (? Due to

improved targeting!?)

– But Expensive … • +- 1500 euro /patient (to compare to drugs …)• Thinking group ongoing at INAMI / RIZIV …

Thank you for your attention!