BREAST CANCER RADIOTHERAPY: CURRENT ISSUES

Dr Jyotirup Goswami

Department of Radiotherapy

Westbank Hospital

The more things change, the more they remain the same:

The target, dose, fractionation and delivery modalities are all changing in breast cancer.

Yet, some of the key questions of yesterday still remain!

NEW STANDARDS OF CARE INRADIOTHERAPY OF BREAST CANCER

Whole breast RT followed by tumor bed boost APBI Conformal RT IMRT & VMAT Hypofractionated RT Changing indications for post-mastectomy

radiotherapy (chest wall & nodal) Prone breast RT

BCS+RT

Mastectomy is no longer a standard of care in breast cancer surgery

BCS is possible in all EBC and is also practised in LABC

Whole breast RT is compulsory in BCT Results of BCS+RT and mastectomy are

equivalent Local control rates are also significantly

improved by use of boost to tumor bed

BCS+RT VS MASTECTOMY: RCTSInstitute IGR Milan NSABP

B-06NCI EORTC Danish

Stage 1 1 1,2 1,2 1,2 1,2,3

Surgery 2cm gross

margin

Quad-rantectom

y

Lump-ectomy

Gross excision

1 cm gross margin

Wide excision

Follow-up(y) 15 20 20 18 10 6

OS:BCS+RT(%) 73 42 46 59 65 79

M(%) 65 41 47 58 66 82

LR: BCS+RT(%) 9 9 14 22 20 3

M(%) 14 2 10 6 12 4

BCS+RT VS BCS

Vinh-Hung et al. JNCI ( 2004);96:115-121

The pooled meta-analysis of 15 RCTs shows a threefold reduction in local failure & a small but significant improvement in OS with RT after BCS

EBCTCG META-ANALYSIS (LANCET 2000)

Meta-analysis of 10 and 20 yr results of 40 RCTs of EBC.

N=20 000 50% node positive Local recurrence

after BCS was reduced by approximately 2/3 with RT, irrespective of type of RT and stage.

Breast cancer mortality was significantly reduced

However, mortality due to other causes was significantly increased.

Absolute increase in 20-yr survival was 2-4% (except those women at very low risk of recurrence).

EBCTCG META-ANALYSIS (LANCET 2005)

78 RCTs of EBC. N= 42 000 7300 had BCS Local recurrence

rate at 5 years, after BCS was reduced by post-op RT from 26% to 7%.

15-yr breast cancer mortality was significantly reduced, from 35.9% to 30.5%

Overall mortality reduction with RT was 5.3% at 15-yrs.

Similar proportional benefit of RT in ALL stages. Absolute benefit varies with the actual risk, according to stage.

BREAST CONSERVATION THERAPY: NODE NEGATIVE DISEASE

EBCTCG Lancet 2005,vol 366, 2093

5 yr gain 16.1%

15 yr gain 5.1%

LR OS

EBCTCG Lancet 2005,vol 366, 2093

5 yr gain 30.1%

15 yr gain 7.1%

LR OS

BREAST CONSERVATION THERAPY:

NODE POSITIVE DISEASE

EBCTCG META-ANALYSIS (LANCET 2011)

17 RCTs of BCS+RT vs BCS alone

N= 10 801 (pN0=7287, pN+=1050)

ANY recurrence rate at 10 years, after BCS was reduced by post-op RT from 35% to 19.3%.

15-yr breast cancer mortality was significantly reduced, from 25.2% to 21.4%

Similar proportional benefit of RT in ALL stages. Absolute benefit varies with the actual risk, according to stage.

BOOST VS NO BOOSTEORTC 22881-10882 TRIAL

Bartelink et al

Planning of boost is largely dependant on localisation method and modality used

Many centres practise clinical planning, especially if electrons are to be used

CT based planning, though preferable, is also problematic

Cavity location is not always clear.

Also the shape and size of the cavity will change, depending on when the image is taken

SEROMA CONTOURING GUIDELINES

STV (Seroma Target Volume)= tumor cavity

CTV= STV+1cm (EDITED from skin and chest wall by 5mm)

PTV=CTV+1cm

STV to EXclude breast tissue stranding, but INclude surgical clips (if present)

Wong et al

BOOST MODALITIES

En-face electrons HDR brachytherapy 3DCRT/IMRT/VMAT IMPT Modulated electrons (MERT)

Electrons are still the commonest and simplest modality. But dosimetrically the most inferior!

HDR brachytherapy is a labour intensive, cosmetically demanding, but dosimetrically excellent alternative for deep-seated tumors. (>3cm from skin)

BOOST DOSIMETRYDE VS MET VS VMAT

Alexander et al

BREAST CONTOURING GUIDELINES

Because more and more centres are doing conformal CT-based planning for breast cancer, contouring guidelines for the intact breast/ chest wall are also increasingly necessary.

The RTOG has come up with a Breast Cancer Atlas.

BREAST CANCER ATLAS

For IIB/III after

NACT & BCS

REGIONAL NODAL CONTOURING

DURING CT SIMULATION

Post-BCS

Post-Mastectomy

Breast-superior

Breast-inferior

SCF begins

Axillary level III begins

Axillary level II begins

Axillary level I begins

Axillary level I ends

IMC begins

IMC ends

APBI

Twin rationale:

(1) Most breast cancer recurrences occur in the index quadrant.

(2) Many patients cannot come for prolonged 5-6 week adjuvant radiotherapy for logistic reasons.

APBI: INDICATIONS (ASTRO RECOMMENDATIONS)

Suitable outside clinical trial

(ALL of) Age>60 years BRCA negative T1N0M0 (pT<2cm) EIC negative Unifocal IDC/ favourable

histology Margin negative (>2mm) LCIS negative ER positive

Suitable only in a clinical trial

(ANY of) Age 50-59 years BRCA negative T1/2,N0,M0 (pT2-3 cm) EIC <3cm Unifocal ILC Margin close (<2mm) ER negative

ASTRO: “UNSUITABLE” FOR APBI

ANY OF:

T>3cm/T4 or N+ BRCA mutated High grade LVSI extensive EIC+ve (>3cm) Multifocal disease (contraindication to BCS

per se) Margin positive Received neoadjuvant chemotherapy

APBI: MODALITIES

Intra-operative electrons (ELIOT) Intra-operative/ peri-operative HDR

interstitial brachytherapy Mammosite Intra-operative orthovoltage X rays (TARGIT)

75432 1112101620

APBI: INTERSTITIAL BRACHYTHERAPY

3D CONFORMAL BRACHYTHERAPY

TARGIT

ELIOT

3DCRT AND IMRT

MAMMOSITE

COMPARISON OF APBI TECHNIQUES

APBI: CLINICAL RESULTS SO FAR

HDR INTERSTITIAL BRACHYTHERAPY:RESULTS

Institution

Dose Dose Rate

Ipsilateral breast

recurrence rate

Cosmesis & Complications

William Beaumont Hospital, USA

32-34 Gy/8-10#

50 Gy

HDR

LDR

2.1% (5-yr)

0.9% (5-yr)

>90% achieved good to excellent cosmesis

Ochsner Clinic, USA

32-34 Gy/8-10#

50 Gy

HDR

LDR

8% 75% achieved good to excellent cosmesis

London Regional Cancer Centre, Ontario, Canada

37.2 Gy/10#

HDR 16.2% at 5 yrs*

Median overall cosmetic score 89%.

HDR INTERSTITIAL BRACHYTHERAPY:RESULTS

Institution

Dose Dose Rate

Ipsilateral breast

recurrence rate

Cosmesis & Complications

National Institute of Oncology, Hungary

30.3-36.4 Gy/7#

HDR 6.7% Excellent to good cosmesis in 84.4%.

Tufts New England, USA

34 Gy/10#

HDR 6.1% (5-yr actuarial)

89% had excellent cosmesis at 5 years.

Guy’s Hospital, London

55 Gy LDR 37%* Cosmesis good to excellent in 85%.

*= inappropriate selection of patients for APBI

MAMMOSITE:RESULTS

Institution Dose Ipsilateral breast

recurrence rate

Cosmesis &Complications

American Society of Breast Surgeons Mammosite Breast Brachytherapy Registry trial (97 institutions)

34 Gy/10#

1.79% 3-yr actuarial LRR

Good-excellent cosmesis in >93%.

Rush University Medical Centre, Chicago, USA

34 Gy/10#

5.7% (crude)

Good-excellent cosmesis in 93%.

IORT:RESULTS

Institution

Dose Modality Ipsilateral breast

recurrence rate

Cosmesis & Complications

European Institute of Oncology, Milan

21 Gy Electrons 1% Mild/severe fibrosis in 3%.

State University of Buffalo, USA

15-20 Gy 120 kV X rays

29% Acceptable

University College, London(TARGIT)

20 Gy 50 kV X rays

0% Acceptable

EBRT (3DCRT): RESULTS

PROSPECTIVE RCTS OF APBI

IMRT BREAST: WHY?

Dosimetric advantages include:

(1) better dose homogeneity for whole breast RT

(2) better coverage of tumor cavity(3) feasibility of SIB

Forward planned IMRT (field-in-field) is preferred as it is simple and effective.

FORWARD PLAN IMRT

Courtesy: Budrukkar A

IMPORT TRIALS (PHASE III RCTS FROM UK)

IMPORT High: (2008-ongoing) To test dose-escalated IMRT

in high-risk EBC after BCS High risk by v/o (ANY)

N+/grade III/T>2/NACT received/margin<5mm/age 18-49 yrs/LVE+

3 arms: WBRT followed by sequential

boost (56 Gy/23#) WBRT with SIB (48Gy/15#) WBRT with SIB (53Gy/15#)

Primary endpoint: Breast fibrosis

IMPORT Low: (2006-2010) To test PBI by IMRT in low-

risk EBC after BCS (ALL) IDC/no ILC/pN0/no

LVE/pT<3cm/unifocal/grade I,II or III/margin>2mm

3 arms: WBRT (15#/3 weeks) WBRT +PBI (each 15#/3

weeks) PBI (15#/3 weeks)

Primary endpoint: Local control (ipsilateral)

HYPOFRACTIONATED RT

Started as an empirical practice in government-run health care systems of UK and Canada

Initially, a purely logistical exercise to reduce treatment duration & create machine space

Recently, 2 large trials, START-A and START-B, have validated that clinically as well, hypofractionated RT is safe and effective.

In fact, even while delivering a lower BED, the hypofractionated regimens have shown a survival advantage over conventional fractionation!

START-A: (1998-2002) N=2236 EBC (pT1-T3a, pN0-N1,

M0) BCS=1900 (85%) &

MRM=336 (15%)3 arms: 50 Gy/25#/5 weeks 41.6 Gy/13#/5 weeks 39 Gy/13#/5 weeks

Median FU=5.1 years

Locoregional relapse rates were 3.6%, 3.5% and 5.2%, respectively

Late effects, based on photographs and patient assessments, were significantly lower with 39 Gy as compared to 50 Gy

This trial estimated α/β of breast cancer as 4.6Gy for tumor control and 3.4Gy for late change in photographic appearance.

Lancet Online. March 19,2008

START-B: (1999-2001) N=2215 EBC (pT1-T3a, pN0-N1,

M0) BCS=2038 (92%) &

MRM=177 (8%)2 arms: 50 Gy/25#/5 weeks 40 Gy/15#/3 weeks

Median FU=6 years

Locoregional relapse rates were 3.3% and 2.2%, respectively

Absolute differences in locoregional relapse was -0.7% (95%CI -1.7% to 0.9%), meaning that with 40Gy the relapse rate would be at most 1% worse and at best 1.7% BETTER!

Lancet Online. March 19,2008

HYPOFRACTIONATION FROM THE RADIOBIOLOGIC VIEWPOINT

UK-FAST: (2004-2007) N=915 Favourable EBCs after

BCS (age>50 yrs, pT<3cm, pN0)

3 arms: 50Gy/25$/5 weeks 28.5Gy/5#/5 weeks

(once-weekly) 30Gy/5#/5 weeks (once-

weekly)

Median FU=37.3 months

Primary end-point was 2 yr change in photographic appearance of breast

3-yr physician assessed moderate to marked breast adverse effects were 9.5%, 11.1% and 17.3% respectively.

Conclusion:At 3 yrs median FU, 28.5Gy/5# (@5.7Gy/#) is comparable to 50Gy/25# for breast adverse effects and significantly milder than 30Gy/5# (@6Gy/#)

Radiotherapy & Oncology. Epub.2011

CHANGING INDICATIONS OF PMRT

New indications include: Any AXLN +ve High grade tumors LVE PNI Age <45-50 years pT>2cm

Scoring systems are often used.

PN1 VS PN2 FOR CHEST WALL RT

Classically, pN2 disease (>=4 positive axillary nodes) was the indication for postmastectomy chest wall RT

Subgroup analysis of the DBCG 82 b&c trials (2007) suggested SIMILAR survival benefit of PMRT for 1-3 vs 4+ LN.

The St Gallen Consensus (2007) is to treat the SCF even for pN1 (1-3 positive axillary nodes)

The SUPREMO trial evaluated the benefit of PMRT in 1-3 axillary lymph node positive patients.

SUPREMO TRIAL(SELECTIVE USE OF

POSTOPERATIVE RADIOTHERAPY AFTER MASTECTOMY)

Started 2006. Expected to complete end-2012.

N=1600 (planned); 1295 randomised so far*

pT1-T3 (+/- multifocal ds), pN0-N1 (not more than 3 AXLN positive), M0 ,post-MRM

No bilateral breast cancer, margins clear (at least 1mm), no IMC nodes

Chemotherapy as required

2 arms: Standard RT to chest wall &

SCF Observation

Objective: To determine the overall survival of intermediate risk patients treated with post-op RT

Primary endpoint: OS, acute & late morbidities

Secondary endpoints: Locoregional recurrence rates, metastasis-free survival, DFS, QoL, cost-effectiveness

*personal communication

IS THERE A ROLE OF AXILLARY NODAL RT?

Axillary nodal RT is no longer indicated if complete axillary dissection (>10 LN sampled) has been performed.

Axillary nodal RT significantly adds to the lymphoedema morbidity

The only possible indications today are: (1) incomplete/ no axillary dissection (2) positive axillary nodes WITH

extracapsular extension (ECE)/ perinodal extension (PNE)

IS SCF RT REQUIRED AT ALL?

Studies suggest that isolated SCF recurrences are uncommon, for both pN1 and pN3 disease

The main risk for pN3 disease, is not SCF recurrence but distant metastasis

PRONE BREAST RT Suitable for pendulous

breasts, where breast-only RT is required.

Results in significantly better coverage of the breast and significant reduction of dose to the ipsilateral lung.

Heart dose remains unchanged.

BUT there is significantly more grade 1-2 dermatitis AND setup error.

Varga et al

THANK YOU