Breast CancerAccelerated Partial Breast

IrradiationBruce G. Haffty, MD

Professor and ChairmanDept Radiation Oncology

UMDNJ-RWJMSCancer Institute of New

Jersey

CHILE

2007

Rationale for Partial Breast Radiation

• The majority of all local recurrences occur within the region of initial lumpectomy

• With or without whole- breast radiation therapy

• Why do we need to radiate the whole-breast

• Early Phase I/II data on partial breast irradiation appears promising for selected patients

CHILE

2007

Potential Benefits of APBI

• Five days versus six weeks• Decrease time and inconvenience of BCT

• Improve underutilization of BCT?

• Improve quality of life?

• Increase local control?

CHILE

2007

Potential Advantages of APBI

• All local therapy completed prior to chemotherapy

• Treatment of tissue at most increased risk of sub-clinical disease – rather than healthy breast tissue/skin may actually improve cosmesis

CHILE

2007

Potential Disadvantages

• Local relapses may be higher

• Fibrosis with larger fractions may be significant with longer follow-up

• Prospective randomized data proving its effectiveness is lacking

PBI-Potential Disadvantages

CHILE

2007

Partial breast irradiation

• Pilot data in selected patients appears promising

• Short follow-up limits definitive conclusions

• Definitive randomized data, as has been done with lumpectomy vs mastectomy and lumpectomy with RT vs lumpectomy alone is lacking

• Currently, plans are underway for pivotal randomized trials

Selection Criteria

Probably acceptable:Invasive lobular, DCIS, EIC, Age ?,1-3 pos. nodes with - ECE

Arthur, Brachytherapy, 2003 - Arthur, J Surg Oncol, 2003

American Brachytherapy Society American Soc. of Breast Surgeons

Age ≥45 yo ≥50 yo

Diagnosis Invasive Ductal CarcinomaInvasive ductal carcinoma or

Ductal carcinoma in situ

Size ≤3cm ≤2cm

Margin status

Negative- no tumor involving inked margin

Negative - at least 2 mm in all directions

Nodal status

Negative axillary lymph node dissection orsentinel lymph node evaluation

Negativeaxillary lymph node dissection or

sentinel lymph node evaluation

APBI margin

Tumor

Ideal target

Surgical margin

? Residual disease extent

micro extension

Target Definition

- Pathologic and clinical failure pattern data

No data available to suggest target is whole breast

CHILE

2007

Partial Breast Irradiation• Interstitial radiation therapy

– Multiple catheters• High dose rate-twice daily over several days

• Low dose rate-temporary implant over 4-7 days

• Mammosite

• Intraoperative electrons

• Intraoperative photon sources

• Conformal external beam radiation

CHILE

2007

Multi-catheter Technique

• Original technique• Results with longest follow-up

- on which everything is based• Most adaptable• New image-guided techniques for catheter

placement available

• Learning curve• Higher degree of dependence on experience• Most breast trauma / potential for pain

CHILE

2007

Multi-Catheter Brachytherapyplacement – US, Stereotactic mammography, or

CT guidance

CHILE

2007

Conventional Breast Brachytherapy

Published Single Institutional Phase II Studies

Interstitial BrachytherapyInvestigator N F/U Local

RecurrencePerera, 1996 27 1.7 y 2.6%

Samuel, 1999 11 5.6 y 0.0%

King, 2000 50 6.3 y 2.0%

Vicini, 2001 174 3.0 y 0.0%

Wazer, 2002 32 2.8 y 3.0%

Polgar, 2002 45 4.8 y 4.4%

CHILE

2007

Partial breast irradiation

• Interest in PBI surged after May, 2002 sparked by the FDA approval of the Mammosite device

• FDA approved the device, not the concept of PBI

• FDA approval was based on concept of the MammoSite as a boost after whole breast RT

• “The safety and effectiveness of the MammoSite RTS as a replacement for whole breast irradiation in the treatment of breast cancer has not been established.”– FDA-www.accessdata.fda.gov

MammoSite Radiation Therapy System

• Design based on Multi-catheter dosimetry– Therefore Multi-cath results apply?

• Easiest approach for patient and Rad Onc team

• **Most widely available and used form of APBI– Reflects simplicity and patient approval

• Requires Surgeon/Rad Onc communication

• Limited ability to adapt – „If it doesn‟t fit, you can manipulate a bit, but then you must quit‟

CHILE

2007

MammoSite Device

Variable 4 to 5 cm balloon

50 – 70 cc

Radiation

source

port

pathway

Injection Port

CHILE

2007

MammoSite Radiation Therapy System

Spherical

4 to 5 cm (35 - 70 cc)

15cm length

6mm diameter

Spherical

4 to 5 cm (35 - 70 cc)

Ellipsoid

CHILE

2007

Percutaneous Post-Op Insertion

US Guided Scar-Entry Technique

Ideal Case for MammoSite

3.4 Gy

4.25 Gy

5.1 Gy

1cm

Placed by Surgeon or Rad Onc – at the time of lumpectomy or post lumpectomy

Target conforms to balloon surface

• 87 institutions• 1237 cases• Median follow-up 5 months• Acceptable technical reproducibility• Cosmetic results at 12 months (92%

good/excellent) and are comparable to those reported with whole breast RT

• Early toxicity rates appear acceptable– infections, radiation recall

ASBS MammoSite Registry TrialVicini et al, Cancer, 104: 1138-48, Sept 2005

CHILE

2007

3D-Conformal External Beam

• Non-invasive• Increased dose homogeneity• Potential for best cosmesis

• Technique with least experience– Dose / dose fractionation?

• Planning process - time consuming• Larger volume of breast treated

CHILE

2007

3D conformal/IMRT

• Early pilot experiences– Vicini - supine

– Formenti - prone

• Accel. dose scheme

• Short follow-up

• Limited patient #‟s

3-D Conformal Radiation

Baglan et al., 2003.

Potential advantages• Non-invasive

• Optimal dose homogeneity

3D conformal/IMRTRTOG-0319, phase I/II, Vicini, completed

Potential disadvantages• Breathing motion• Patient set-up error• Volume of breast tissue tx

External Conformal-Target Volumes(Vicini et al.RTOG-0319, Int J Rad Onc. 63:5:2005)

CHILE

2007

3D-CRT Experience

Institution#

CasesF/U

(months)Fractionation

SchemeLocal

Recurrence

Cosmetic Result-

Good/Excellent

William Beaumont Hospital

Baglan, IJROBP, 20039

8(median)

340 or 385 cGy x10(b.i.d. over 5 days)

0% 100%

William Beaumont Hospital

Vicini, IJROBP, 200331

10(median)

340 or 385 cGy x 10

(b.i.d. over 5 days)0% 100%

New York University/Keck School of Medicine

Formenti, IJROBP, 2004

4718

(median)6 Gy x 5 (10 days) 0% 100%

Mammosite vs 3D Conformal

3D-CRT• Able to protract • Smaller fraction size• Respiratory motion, patient

setup –

• Large volume

MammoSite• Momentum, reports of

already being done• Larger fraction size

• Limited volume

Fractionation Schedule

• For High Dose Rate Interstitial and Mammosite– 3.4 Gy Twice Daily X10-34G/1 week

• For External Beam Conformal– 3.85 Gy Twice Daily X10-38.5 Gy/1 week

• For Intraoperative – Single Dose of Approximately 20 Gy

W hole Breast Irrad iation

Boost to 60 Gy

6 w eeks

IO RT

21 G y in 21 M inutes

IDC Less than 2.5 cm

N = 824

European Institute of OncologyRandomized Trial

Start 1/02 – End 9/04

IORT: European Institute of Oncology

Veronesi et al.

21 Gy in 21

minutes

WBI

50-50.4Gy in 25-28 fractions to whole breast, followed by

electron boost to surgical bed with margin of 60-66.4 Gy

APBI34 Gy in 3.4 Gy bid x 5 tx days

Interstitial Brachytherapy or

Mammosite Balloon Catheteror

38.5 Gy in 3.85 Gy bid x 5 tx days3D Conformal External Beam

VS

Eligible patient treated with lumpectomyPost-Lumpectomy CT evaluation

Randomization

Stratification

Disease stage: 0 vs I/II node– vs I/II node+Menopausal statusHormone receptor status Intention to receive chemotherapy

NSABP B39 / RTOG 0413 -overview

Patient Eligibility• All Ages

• Primary lesion– Unicentric (if multifocal < 3cm total)– Stage 0, I, II breast cancer (If stage II ≤ 3 cm)– DCIS or Invasive Adenocarcinoma– Negative micro. resection margin (NSABP definition)

• Axillary nodes ― 0 - 3 positive without ECE– ALND (≥6 nodes required) or negative SLN

• Target evaluation– Clearly identifiable target– Lumpectomy cavity/whole breast volume ≤30% based on

post-lumpectomy CT scan

• Timing– Randomization within 42 days of last surgery

NSABP B39 / RTOG 0413 -overview

NSABP B39 / RTOG 0413 -overview

Study Aims

• Primary Aim−To compare In-Breast Tumor Control−To determine if PBI is equivalent to WBI

• Secondary Aims−To compare OVS, DFS, DDFS−To compare Quality of Life

»Cosmetic outcome»Fatigue and treatment related symptoms» Perceived convenience of care»Acute and Late toxicities

NSABP Sample Size Considerations

• Estimated 6.1% 10-year cumulative incidence of IBTR for WBT

(hazard of 7.8 IBTR/1000 pt-year, based on 11 previous NSABP trials)

• Analyze when 175 IBTRs (about 11 years after trial opens)

• Anticipated activation: Winter 2005

CHILE

2007

Phase III Clinical StudiesInstitution/Trial

TrialDesign

#Cases

ControlArm

ExperimentalArm

Status

NSABP B 39RTOG 0413

Equivalence 300050-50.4 Gy WB+/- 10-16 Gy

Boost

(1)Interstitial Brachytx, or

(2) MammoSite, or(3) 3D Conformal EBRT

Not YetActivated

National Institute of Oncology

Budapest, Hungary

Non-Inferiority

570 50 Gy WB(1)Interstitial Brachytx

(5.2 Gy X 7) or(2) Electrons (50 Gy)

255Enrolled

European Brachytherapy Breast Cancer GEC-ESTRO

Working Group

Non inferiority,

Non irrelevant

3% Difference

117050-50.4 Gy WB+ 10 Gy Boost

Brachytherapy Only32.0 Gy 8 fractions

HDR30.3 Gy 7 fractions

HDR50 Gy PDR

ActivatedMay 2004

European Institute of Oncology

Equivalence 82450 Gy WB

+ 10 Gy Boost

Intra-operativeSingle fraction EBRT

21 Gy x 1

587 Patients Enrolled

University College of London

Equivalence 1600WB RT

(per center)+ Boost

Intra-operativeSingle fraction EBRT

5 Gy x 1

110Enrolled

Christie Hospital/Holt Radium Institute

N.S. 70840 Gy in 15 fractions WB(no boost)

500 – 531 cGy x 8 (10 days)

Completed

Phase III protocol -Why become involved?

• Appropriate Phase III data needed to establish APBI as standard of care– If for – get involved to prove appropriate

– If against – get involved to prove inappropriate

• Guidelines for all 3 APBI techniques

• QA program – assures facilities follow basic rules of

target coverage – dose delivery

– quickly brings your facility to advanced level

CHILE

2007

Partial breast irradiation

• Currently, we are limiting this treatment to selected patients on prospective trials

– RTOG/NSABP Randomized trial of whole breast verses partial breast

– Considering other phase I/II options for selected patients

CHILE

2007

Partial Breast Irradiation

• Treatment with partial breast irradiation, in my view, remains investigational-remember the FDA statement– “The safety and effectiveness of the MammoSite RTS as a replacement for whole breast irradiation in the treatment of breast cancer has not been established”

CHILE

2007

Partial Breast Irradiaton

• Participation in prospective trials evaluating PBI is encouraged

• NSABP/RTOG randomized whole breast verses partial breast

• ACOSOG repeat partial breast for local relapse

• Other prospective institutional trials addressing critical issues in PBI– Dose escalation– Positioning– Alternative techniques

CHILE

2007

Thank You Congreso de la Sociedad Chilena de Mastologia

Bruce G. Haffty, MD