New Irradiation techniques in

non metastatic breast cancer

Dr.zhaleh karimimoghaddam

Assistant professor of Radiation Oncology

Of Zanjan University of Medical Science

Introduction

1. APBI

2. Hypo fractionation

Why PBI?

1. decreases breast recurrence → longer survival

NSABP trial (B-06)from large well-controlled RCT after 20 yr f/u reported that :the same result in OS & LC in MRM vs. BCS+WBI but

-more cancer related death in MRM group

-more vascular death in BCS+WBI group

After BCS and whole-breast RT, most of

ipsilateral breast tumor recurrences

(IBTR) occur in the primary tumor

cavity and can be classified into two main

categories; true recurrences and

elsewhere recurrences.

Prospective Randomised

Trials of Lumpectomy+/- XRT

Trial % off patients recurring

L alone L+XRT

NSABP B-06 36 12

Milan 24 6

Scottish 25 6

Overall,, whole breast RT decreases breast recurrence by a factor off 3 or 4..

Recurrences are predominantly at the site off the original cancer

Whole Breast Radiotherapy Reduces Local

failure

Why PBI?

2)minimize PTV→ reduction in treatment

toxicity NSABP B-06 → 1,039 patients → were treated with lumpectomy

it was reported through follow-up that 75% of local recurrences occurred at or

near the lumpectomy site and that WBRT was irrelevant to the findings .

Freedman et al.

reported on IBTR following BCS and WBI in 1,990 for women with stages 0-

II

breast cancer with a median follow-up period of 6.7 years.

They classified recurrences according to their location.

The 15-year actuarial rate of a true/marginal recurrence was 7% compared

with an elsewhere recurrence rate of 6%

Recurrence Pattern 91% of local recurrence after breast conserving therapy

occurs near the site of the primary tumor, even when

radiotherapy is not given.

Thus, the occult tumors in other quadrants may remain

dormant, never becoming clinically relevant; and

radiotherapy to the site of the original tumor may be

adequate

Fisher et al Samsung Oncology 1992;8:161.

Veronesi et al N Engl J Med 1993;328:1587

Why PBI?

3)shorter treatment time

Accelerated PBI (APBI)with shorter duration of

RT usually one week therefore:

-fewer transport

-lower cost

-quickly start of systemic therapy

Why PBI?

4)better cosmetic results

lesser irradiated volume and

fewer telangectasis and fibrosis

Accelerated Partial Breast Irradiation

Rationale Most recurrences occur within 2cm of lumpectomy from prospective and RND trials (>2/3 1st failure)

Decreased Treatment time and QOL

Potential reduction in treatment toxicity

Multiple different techniques with short follow up

APBI Established methods

External beam (3.85gy BID x 5 days)

Most common in USA

Interstitial Brachytherapy: LDR, HDR

Multi-catheter

Intracavitary:

Intraoperative Electrons: ELIOT

Intraoperative Orthovoltage Photons: TARGIT-A

Mammosite

NSABP B39 / RTOG 0413

>4300pts accrued

Tis-T2,N1-3

<3cm

WBRT 50-50.4Gy/25-28f +10-16Gy

Boost

38.5Gy/10f 3DCRT or 34Gy/10fMammosite

or multilumen BT

Stratified

ER status

DCIS/invasive/n1

Menopausal

Chemotherapy

• Primary Endpoint: IBTR

•Secondary:

OS, recurrence free survival

•Awaiting initial results 15 sept 2015 now closed to accrual.

External beam APBI:

Initial cosmetic results from RAPID

RAPID (Olivotto et al) WBRT

vs. APBI No IBTR results yet

Worse patient reported cosmesis in

ABPI from physician, nurse, and

patient 36mo median FU

J Clin Oncol. 2013 Nov

10;31(32):4038-45. doi:

10.1200/JCO.2013.50.5511. Epub

2013 Jul 8.

a multicenter randomized trial

2135 women

>40yr

DCIS or Invasive

<3cm

Node Neg

WBRT 50gy/25 or 42.5/16 +/-

Boost

3DCAPBI

38.5gy/10BID

RAPID

Results : Between 2006 and 2011, 2,135 women were

randomly assigned to 3D-CRT APBI or WBI. Median

follow-up was 36 months. Adverse cosmetic at 3 years

was increased among those treated with APBI

compared with WBI as assessed by trained nurses (29%

v 17%; P < .001), by patients (26% v 18%; P = .0022),

and by physicians reviewing digital photographs (35% v

17%; P < .001). Grade 3 toxicities were rare in both

treatment arms (1.4% v 0%), but grade 1 and 2

toxicities were increased among those who received

APBI compared with WBI (P < .001).

Mammosite Single lumen catheter

Typical dose (and on NSABP B31) RT: 34 Gy in 3.4 Gy fractions, prescribed 1 cm from balloon

About 20% of RND trial

Needed balloon-to-skin dist >5 mm, cavity size < 6 cm

Results at 3 years from registry: IBTR = 2.15% (4 yr=2.65%)

3 yr axillary recurrence = 0.36% (4 yr=0.6%)

DM=1.1%

OS=95.6%

•Toxicity: infection: 9.5%,

Seroma: 27% (13% symptomatic)

2% fat necrosis

Cosmesis: Good or excellent at 4 yrs: 91%

Conclusions: Data consistent with other APBI techniques

Nelson (Am Soc Br Surgeons, Am J Surg 2009)

Interstitial APBI Matched Pair: Intersitial PBI vs. WBI

Methods: 199 pts with early-stage breast CA (Stage I/II)

RT: LDR 50 Gy at 0.52 Gy/hr (60%) or HDR 32 Gy in 4 Gy or 34 Gy in 3.4 Gy

Cosmesis: Good to excellent in 98.3% of pts

Antonucci, Beaumont, IJROBP 2009

Results of randomized and single-arm

interstitial brachytherapy trials

Intraoperative APBI

Targeted intraoperative radiotherapy versus

whole breast radiotherapy for breast cancer

(TARGIT-A trial): an international,

prospective, randomized, non-inferiority phase

III trial

Methods:

70% median FU 2.5 years

The primary outcome was ipsilateral

local failure

Device summary Low energy x-rays (50

kV maximum) placed at the at the tip the

tumor bed

Dose to the surface of the tumor bed was

20Gy falling sharply to 5Gy at 1cm depth

from resection margin

WBRT delivered from 46-66Gy

depending on institution and policies for

“boost”

TARGIT-A randomized trial.

Lancet.2014;383(9917):603–13.

Stratified

3452 pts

>45yo

cN0, -LVI/G1/2

TARGIT Post op Add WBRT for

LVI, Grade 3, Nodes

WBRT+boost

46-66Gy

Targit A: 2014

Intraoperative radiotherapy versus

external radiotherapy for early breast

cancer (ELIOT): a randomized

controlled equivalence trial(2013) (ELIOT): a randomized controlled equivalence trial. Lancet

Oncology. 2013;14(13):1269–77.

Key differences from TARGIT

Done in Italy only

IORT 21Gy with Electrons vs

50Gy+10Gy boost

Resultes 5y IBTR WBRT: 0.4%

5y IBTR Intraop: 4.4%

OS same

Intra-op Conclusions

Randomized data demonstrate safety and efficacy

Allows post-surgery RT for high risk groups without toxicity

Statistically Significant increase LRR vs WBRT

Long term data still lacking

Continue to follow patients….

ESMO Clinical Practice

Guidelines 2015

in the ELIOT (single dose of electrons) and

TARGIT (single intra-operative dose 50 kV X-rays) randomized trials, the ipsilateral breast recurrence

rate was significantly

higher in the APBI groups, compared with the WBRT trial

Results 5y IBTR WBRT: 0.4%

5y IBTR Intraop: 4.4%

ASTRO taskforce for APBI

Suitable group

age≥60

N 0

T1 primary cancers

Positive ER status

negative lymph vascular space invasion (LVSI)

widely negative margins (>2mm)

no multicentricity

ASTRO taskforce for APBI Cautionary group

age <60

T2 primary disease

pure DCIS <3 cm,

close margins (<2 mm),

focal LVSI

multifocal or multicentric disease

invasive lobular carcinoma

or ER negativity

ASTRO taskforce for APBI

Unsuitable group

tumor size >3 cm

positive margins

any positive lymph nodes or no axillary surgery

extensive LVSI

multicentricity

DCIS >3cm

or the presence of a BRCA1 or 2 mutation

Patient selection criteria for accelerated partial breast irradiation(APBI)

Conclusion

Currently, the standard of care after BCS is still WBI, not APBI. However,

the role

of APBI will continue to be defined by the mature results of ongoing randomized

trials from large cooperative groups in the next 5–10 years.

Hypo fractionation

ASTRO criteria for HF :

Age ≥ 50 years at the time of diagnosis; had a first and only diagnosis of breast cancer;

pT1-T2N0 patients based on the American Joint Committee on Cancer TNM staging classification were treated with breast-conserving surgery; and did not receive chemotherapy.

four large multicenter randomized

clinical trials were conducted;

one in Canada and three in England: the Ontario

Clinical Oncology Group (OCOG) Trial. the Royal Marsden

Hospital/

Gloucester Oncology Centre (RMH/GOC) Trial, the UK

Standardization

of Breast Radiotherapy Trial A (START A), and the UK

Standardization of

Breast Radiotherapy Trial B (START B).

Inclusion criteria, dose and fraction properties, local control and survival rates

in

randomized large hypo fractionation trials Study Inclusion criteria Total dose

(Gy)/fraction/

time

Local recurrence (%)

5 y/10 y

Survival (%)

5 y/10 y

OCOG

n =1,234

BCS

T1-T2, N0, M0

<25 cm width

Uninvolved inked

margin

50 Gy/25/35 d

42.5 Gy/16/22 d

3.2%/6.7%

2.8%/6.2%

91.7%/84.4%

92.3%/84.6%

RMH/GOC

n = 1,410

BCS

T1-3, N0-1, M0

Complete

Macroscopic

resection

50 Gy/25/5 wk

42.9/13/5 wk

39 Gy/13/5 wk

7.9%/12.1%

7.1%/9.6%

9.1%/14.8%

START A

n = 2,236

BCS or mastectomy

T1-3,N0-1, M0

Clear tumor

margins >1 mm

50 Gy/25/5 wk

41.6 Gy/13/5 wk

39 Gy/13/5 wk

3.6%

3.5%

5.2%

88.8%

88.1%

88.7%

START B

n = 2,215

BCS or mastectomy

T1-3, N0-1

Clear tumor

margins >1 mm

50 Gy/25/5 wk

40 Gy/15/3 wk

3.3%

2.2%

87.5%

90.4%

Skin toxicity and cosmetic outcome rates in large

randomized hypo fractionation trials Study n Total dose

(Gy)/fraction/time

Toxicities skin (%)

5y/10y

Excellent/good

cosmesis or no

change (%)

Adverse cosmetic

results (%) 5y/10y

OCOG

n = 1,234

50 Gy/25/35 d

42.5 Gy/16/22 d

17.7%/29.5%

13.9%/33.2%

79.2%/71.3%

77.9%/69.8%

20.8%/28.7%

22.1%/30.2%

RMH/GOC

n = 1,410

50 Gy/25/5 wk

42.9/13/5 wk

39 Gy/13/5 wk

12.0%/18.1%

13.0%/18.0%

5.6%/12.0%

60.4%/46.6%

54.3%/42.0%

69.7%/43.9%

60.4%/46.6%

54.3%/42.0%

69.7%/43.9%

START A

n = 2,236

50 Gy/25/5 wk

41.6 Gy/13/5 wk

39 Gy/13/5 wk

31.1%

25.0%

2.6%

59.0%

58.1%

65.9%

42.9%

43.6%

32.1%

START B

n = 2,215

50 Gy/25/5 wk

40 Gy/15/3 wk

42.3%

38.2%

58.8%

64.5%

42.2%

36.5%

According to the data obtained in all

these randomized trials, standard and

HF treatment models revealed similar

results with regard to local recurrence,

survival,

and adverse cosmetic results.

Systematic review and meta-analysis

comparing hypo fractionated

with conventional fraction radiotherapy in

treatment of early breast cancer (23 studies)

Surgical Oncology(8 June 2015),china

Meta-analysis demonstrated

hypo fractionation

radiotherapy (HFRT) was associated with

decreased grade 2/3 acute skin reactions

compared with

conventional fraction RT (CFRT), either 2.5-

3.0 Gy per fraction or 5.0-6.5 Gy per fraction.

HFRT with 2.5-3.0 Gy per fraction significantly

decreased moderate/marked photographic changes

in breast appearance

compared with CFRT while HFRT with more than

3.0 Gy

per fraction significantly increased

moderate/marked photographic changes.

HFRT cost one-third lower than CFRT.

local regional recurrence,

distant metastasis, overall survival, disease free

survival, excellent/good cosmetic comes,

symptomatic radiation pneumonitis, ischemic

heart disease and symptomatic rib fracture,

there was no significant

difference between two arms.

Where is boost location in HF?

tumor bed boost

14 Gy/7 fractions in RMH/GOC trials

10 Gy/5 fractions in the START A and B trials

no patients were given boost irradiation in the

Canadian trials

ASTRO guideline stated that “the task force

agreed that the use of HF-WBI alone (without

a boost) is not appropriate when a tumor bed

boost is thought to be indicated

tumor bed boost (NCCN 2016)

Recommended in patients with higher risk

characteristics (such as age<50,high grade

disease, or patients with focally positive

margins) in order to reduce local relapse.

typical boost doses are 10 to 16 Gy in 4 to 8

fraction.

RTOG 1005 (2014)

A Phase III Trial Of Accelerated Whole Breast

Irradiation With Hypo fractionation Plus

Concurrent Boost Versus Standard Whole

Breast Irradiation Plus Sequential Boost For

Early-Stage Breast Cancer

To determine whether an accelerated course of

hypo fractionated WBI including a

concomitant boost to the tumor bed in 15

fractions following lumpectomy will prove to be

non-inferior in local control to a regimen of

standard WBI with a sequential boost following

lumpectomy for early-stage breast cancer

patients.

“Don’t initiate whole breast radiotherapy

as a part of breast conservation

therapy in women age ≥50 with

early stage invasive breast cancer

without considering shorter treatment schedules.”

ASTRO Guidelines

Conclusions:

Based on available evidence, HFRT with 2.5-3.0 Gy

per fraction should be the better choice for treatment of

early breast cancer patients.

THE END