APBI

ACCELERATED PARTIAL BREAST IRRADIATION

Zvi Bernstein M.D. Zina Memorial Lisod Cancer Hospital

History
Radical mastectomy Halsted (10%LF) Simple mastectomy (10% LF) Lumpectomy + WB XRT (10% LF) Partial breast irradiation ( ?????) Lumpectomy alone 25-40% LF
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1970

2000

Maximal tolerable treatment

Minimal effective treatment

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Novel approaches to the treatment of breast cancer

Systemic therapy:
Novel prognostic parameters Hormonal therapy New chemotherapeutic agents Targeted therapies

Local therapy: Surgery (BCS, SLNBx) Radiation therapy (APBI)

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Breast Cancer: Critical Benchmark Studies

NASBP (NEJM 2002: 347 1233-1241) 20 year F/U shows lumpectomy + XRT 14% LRR lumpectomy alone 39.2% LRR Milan (Ann Oncol 2001 12 : 997-1003) Quadrantectomy + XRT 5.8% LRR Quadrantectomy alone 23.5% LRR Meta-Analysis from Lancet 12/05

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Meta-Analysis Data on Breast Radiotherapy strongly suggests that in addition to improving local control, radiotherapy ALSO improves survival

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The Standard: Whole breast lymphatic drainage irradiation:

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Conventional Breast Irradiation

5 - 6.5 weeks Good excellent cosmetic results Minimal toxicity Local control rates > 90% EORTC 22881 (Bartelink et al, NEJM 2001) > 50 yrs: 1.4% - 3% < 50 yrs: 10%

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Partial Breast Irradiation: Why ?

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Accelerated Partial Breast Irradiation

(APBI):
Definition
Delivery of larger doses/fx of RT to the lumpectomy cavity after BCS in patients with early stage BC using BT , EBRT or IORT. Complete RT in 1- 5 days instead of 6-7wks

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APBI: Scientific Rationale

Distribution of tumor cells confined to a limited area of 1-2 cm around the index lesion and most local recurrences occur at or near the tumor bed Rate of recurrences away from tumor bed (elsewhere failure) equals rate of new primary cancers, or after lumpectomy followed by whole breast RT More convenient for the patient Less expensive (?)

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Question

Does the entire breast need to be treated?

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> 50% of early invasive breast cancers may have limited extent

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APBI prerequisites:
Appropriate technology Appropriately selected patients Accurate target delineation Proven dose coverage QA

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Its a reality
Many centers in the US & Europe already carry out APBI on a regular basis

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Interstitial BT: Clinical Outcome

European experience, LDR/HDR, properly selected pts (397): Median FUP: 1-7 yrs LF: 2% (8/397)
EF: 1.3% (5)

Excellent/good cosmesis: 84%-92%

North American experience, LDR/HDR, properly selected pts (514): Median FUP: 23 91 mos 5 yr actuarial LF: 0% - 6% EF: 0% - 6%
Seminars Radiat Oncol, April 2005

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IORT with Electrons (ELIOT)

Instituto Europeo di Oncologia
1999 2003; median FUP: 20 mos # pts: 590; mean age: 59 yrs T < 2.5 cm Dose: 21 Gy (equivalent to 58-60Gy standard fx) Fibrosis: 19 pts (3.2%) LR: 3 pts (0.5%) Ipsilateral Ca: 3 pts (0.5%) Axillary LN mets: 1 pt (0.2%) Contralateral Ca: 5 pts (0.8%) Distant mets: 13 pts (2.2%) Deaths: 1 pt (0.2%)
Annals Surg 242: 101, 2005
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IORT with Electrons (ELIOT)

Instituto Europeo di Oncologia
Update: Saint Gallen Meeting, March 2008 LR 0.5% ER 0.5% Exactly the same as in 2007

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RTOG 95-17 (Phase II, MS-BT after Lumpectomy)

Toxicity Analysis
Study period: 1997-2000 Number of patients: 100 (evaluated: 99) LDR: 33 HDR: 66 Median follow-up: 2.7 yrs (range: 0.6-4.4 yrs) Grade 3-4 Acute Toxicity: LDR: 9% HDR: 3% Grade 3 Late Toxicity: LDR: 18% HDR: 4% Greater rate of Gr 3 toxicity in pts receiving chemotherapy
Kuske RR et al. IJROBP 65:45-51, 2006
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Leading Phase III Trials of APBI

Trial NSABP B-39 RTOG 0413 T 0-1-2 (< 3 cm) N 0-1 (< 3 + LN) TARGIT T < 3 cm; N 0 ELIOT T < 2.5 cm UK import low GEC-ESTRO Target accrual 3000 Partial breast test arms Multi-source Ir-192 (34 Gy) Single source I-192 (34 Gy) 3D-EBRT (38.5 Gy/10 fx) Time 5d 5d 5-10d

2232

IORT x-rays (20 Gy, surface)

1d

2000

IORT electrons (21 Gy, @ 90%)

1d

2100 1170

IMRT Multi-source Ir-192 (HDR) Multi-source Ir-192 (PDR)

3w 4d 3d

RAPID 21

( OCOG )

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3D CRT (38.5Gy/10 fx)

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NSABP B39-RTOG 0413 Trial

Clear definitions of Patient eligibility (age - > 18 !!!) Pathology assessment Radiology assessment RT target volumes RT dose fractionation schedule RT technique End points (LRC, OS, DFS, cosmesis, toxicity, QOL)

3/05: Opened for accrual: 4/06: 1100 pts, 250 Depts

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Intensity Modulated & Partial Breast Radiotherapy (IMPORT) Trial

IMPORT LOW Trial (N=1935)

Control Test 1 Test 2

40Gy/15Fr
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40Gy/15Fr 36Gy/15Fr
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Budapest Phase III Trial (1998-2004)

# patients: 258 T 1 N 0-1 mic Non lobular, no EIC 50Gy WBI Vs 7x5.2Gy HDR BT or 50Gy localized field, by electrons Median FUP: 60 months Local control: ~ 95% in both arms OS,CSS,DFS no difference Better cosmetic outcome in PBI arm

Polgar, ESTRO 25, October 2006, Leipzig

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APBI: Open Questions

Patient selection (criteria?) Optimal technique ? Optimal schedule (BED values !) Volume definition (QA !) Long term local control ? Risk of long term toxicity ?

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Patient Selection Criteria

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Patient Selection Critical Issue !!

Absence of calcifications/tumor density beyond 1cm from index lesion on mammography Absence of tumor foci in outer 1cm of the surgical margin on pathology Non multi-centric or EIC ++ tumor on imaging/pathology 2 cm grossly tumor free surgical margin 5-10 mm histologically tumor free margin

Holland, ESTRO 25, Leipzig

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If carefully selected
Accuracy of identifying Breast Cancer with Limited Extent may be as high as 90%

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APBI: Patient Selection

ABS: Age > 45 yrs Invasive duct Ca only Tu size < 3 cm Negative margins Negative axilla

Amer Soc Breast Surgeons: Age > 50 yrs Invasive duct Ca or DCIS Tu size < 2 cm Microscopic margins>2 mm Negative axilla

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APBI: Exclusion Criteria

Extensive intra-ductal component Positive axillary nodal status Infiltrating lobular histology DCIS (?) * Young age
Am Soc breast Surg MammoSite Clinical trial for DCIS

Annals Surg Oncol 13:967, 2006

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DiFronzo, L. A. et al. Arch Surg 2005;140:787-794.

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Targeted intra-operative radiation therapy TARGIT

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Targit Patient Selection

Eligibility criteria Age 40 or over (ELIOT: > 48 yrs) Invasive breast cancer 3 centimeters or less (ELIOT: < 2.5 cm) Treatable with lumpectomy Exclusion criteria Bilateral cancer, history of cancer in the same breast Multifocal or multicentric breast cancer Extensive non-invasive cancer (DCIS) Evidence of lymph node metastasis Collagen diseases,other contraindications to breast RT

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IMPORT LOW: Inclusion Criteria

Age 50 Primary breast conservation Unifocal 2.0 cm Invasive adenocarcinoma (lobular ca excluded) Grade 1 or 2 Microscopic clearance 2 mm Node negative No lymphovascular invasion No concomitant CT allowed (sequential CT allowed)

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RAPID Patient Selection

Age > 40 T < 3 cm Invasive carcinoma (non lobular !) or DCIS Non multifocal - multicentric Clear resection margins Negative axilla (dissection or SLN BX) No BRCA carrier

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TECHNIQUE

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APBI: Techniques
HDR-BT Balloon catheter BT (MammoSite) Multi-catheter interstitial BT EBRT 3D CRT IMRT IORT Orthovoltage (50 kv, spherical device) Electrons Brachyterapy

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Advantages of Interstitial BT
Final pathology report available Final microscopic margins Axillary nodal status Optimal coverage of tumor bed (with CT guided insertions)

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Ultrasound-guided needle insertion

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Typical catheter distribution with supine ultrasound guidance

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Open Cavity Technique

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Prone Patient Position

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MammoSite

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IORT
Advantage: Local treatment Surgery, Sentinel lymph node mapping and biopsy and RT is completed in ONE DAY Disadvantages: Single large dose (BED ?) Lack of final pathology results QA - difficult Lack of long term follow-up

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3D - IMRT

Advantage: Availability Disadvantage: Larger volume exposed to RT

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Dose - Schedule

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APBI: Dose/schedule
HDR - Brachytherapy 32-34 Gy/8-10 fx/4-5 days (= 55 Gy/120-144 hrs, LDR) IORT Electrons (IOERT): 21 Gy/1 fx X-rays (50 kv.) 20 Gy/1 fx @ surface 5.0 Gy/1 fx @ 1.0 cm 0.2 Gy/1 fx @ 0.2 cm

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IOERT: Radiobiological Considerations (1)

Giving IOERT immediately after surgery may avoid the problem of accelerated repopulation Tissues treated during surgery still have rich vasculature and aerobic metabolism (before postoperative changes), which make them more sensitive to radiation (oxygen effect)

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IOERT: Radiobiological Considerations (2)

According to the linear-quadratic model and assuming the following alpha-beta ratios: - breast tumor cells = 10 - late responding tissues = 3 21 Gy/1fx = 56Gy/28fx in terms of local control 21 Gy/1 fx = 100 Gy/50 fx (!!) in terms of late effects in normal tissues

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IORT (electrons and low energy x-rays):

Long Term Complications ?
Skin ? Subcutaneous tissues (fibrosis) ? Ribs (bone necrosis) ? Lung (pneumonitis; 2nd primary tumor) ? Heart ? - Mostly short term toxicity data available - Information at present time is lacking and is based on animal studies and radiobiological assumptions and estimations - Long term follow up needed !

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Volume Definition
Still an open question !

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NSABP-RTOG Guidelines

CTV is + 15 mm in interstitial multi-catheter BT + 10 mm in Mammo-Site + 15 mm in 3D CRT (+ 10 mm to PTV)

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APBI at RAMBAM HCC

HDR interstitial BT IOERT EBRT 3D CRT

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Criteria for patient selection:

Age > 60 (> 50 , according to recent amendment) Invasive Ductal Carcinoma. < 2 cm in greatest diameter by pathology. Without EIC. Resection with negative margins > 2 mm. Positive Estrogen/Progesterone receptors (not required, according to recent amendment) Negative axillary lymph nodes (by axillary dissection or SLNB). Patients informed consent.

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HDR interstitial BT at RHCC

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APBI by HDR-BT at RHCC: Principles of Technique

CT scan for target volume definition and delineation. Implant geometry designed according to the rules of Paris System. Nucletron RABBIT template for needle insertion, under local anesthesia.

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Paris System Rules

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Target volume definition and delineation

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Virtual planning

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Interstitial Implant

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TREATMENT PLANNING

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CT Treatment Plan and 2D orthogonal films

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Post-implant CT verification

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Outcome and Toxicity

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IOERT
Intra-Operative Electron Beam Radiation Therapy

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External Beam APBI (1)

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External Beam APBI (1)

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APBI - Conclusions:
5 yr results with APBI have so far produced excellent results: In appropriately selected patients High quality RT delivery and reproducibility required Additional studies needed to clarify: Better selection of candidates Required treatment margins Technical aspects Best technique for each setting

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