The 5th Annual Update in Breakthrough in Hematology and Oncology (AUBHO 2015)

28-29th August 2015 At the Nai Lert Park

Swissotel Bangkok ,Thailand

Updates in Radiotherapy for Breast Cancer

Prasert

Lertsanguansinchai,M.D. Radiation Oncologist Wattanosoth Hospital

50 Years of Advances in Radiotherapy for Breast cancer

Radiation Therapy (RT) : What have we Learned ?

Where are we Now ?

Where are we Going ?

What have we learned ?

Breast Cancer

Radiation Therapy (RT) 50 years ag0

The overview of eight unconfounded randomized trials of radiotherapy initiated before 1975

(total 7,941 women)

Surgery = radical mastectomy or simple

mastectomy

None of the patients received chemotherapy

Surgery alone VS Surgery + Radiation

J. Cuzick JCO 12: 447-453,1994

JCO 12 : 447-453,1994

The overall mortality rate was similar in the first 10 years .A divergence in favor of patients not given radiotherapy is apparent

after approximately 15 years in the radical mastectomy trials .

For the simple mastectomy trials, the overall survival curves remain similar after 10 and 20 years.

Where are we now ?

Breast Cancer

Radiation Therapy (RT)

Tumor Biology

Breast cancer is a systemic disease needs

1.Locoregional control.

2.Prevent and get rid of microdistant metastasis.

Local Radiation Treatment

The additional of radiotherapy to surgery resulted in an improvement rate of local recurrence by ⅔ to ¾ (70%) as compare to surgery alone.

Radiation contribute to improve overall survival when combined with systemic therapy.

NEJM 1995 ; 333 : 1444-1455

Lancet 2000 ; 355 ; 1757-1770

Radiotherapy after Mastectomy and axillary clearance

5-Y Isolated LRR No PMRT PMRT

Node-negative 6.3% 2.3% (p=0.0002)

No significant reduction in 15 year breast cancer mortality

Node-positive 22.8% 5.8%

15-Y breast cancer mortality 60.1% 54.7% (reduction 5.4%)(p=0.0002)

15-y overall mortality reduction 4.4 % (p=0.0009)

EBCTCG PMRT

BCS alone BCS + RT

5-Y LRR 26% 7% (reduction 19%)

15-Y breast cancer mortality 35.9% 30.5% (reduction 5.4%)(p=0.0002)

Radiotherapy after BCS (7311 women in 10 trials),

most had node-negative disease

15-y overall mortality reduction 5.3% p=0.005

EBCTCG BCT

50 Years of Progress :

Integration of RT with surgery and systemic treatment has made RT more effective.

Postmastectomy Radiation in high risk disease improve locoregional control.

Combining BCS and Breast RT (BCT) as an alternative to mastectomy.

Where are we going ?

Breast Cancer

Radiation Therapy (RT)

Postmastectomy Radiation :- 45-50.4 Gy /25-28F in 5-51/2 weeks.

Conserving Breast Surgery followed by whole breast irradiation 45-50.4Gy/25-28F in 5-51/2 wks with/without tumor bed boost 10-16Gy/5-8F in 1-1 1/2 weeks (total 5-6 ½ wks).

However, for convinence and cost, hypofractionated RT for breast has been explored.

Lancet 2005; 366:2087-2106

Radiation Schedules

CANADA START A START B

Energy Co-60, 4-6 MV 6 MV 6MV 2D + Wedge Yes Yes Yes Planning 2D 2D/3DCRT 2D/3DCRT Central Axis Dose +/- 7% +/- 5% +/- 5% Tumor bed boost 0% 61 % 39 % Boost dose - 10 Gy/5 F 10 Gy/5F Energy of boost - Electron Electron Regional nodal RT 0 % 14.2% 7.3 %

The Breast 19 ( 2010) : 163-167

Hypofractionation WBI VS CONVENTIONAL WBI

Median FU IBTR LRR DFS OS

CANADA 12 yrs 50Gy/25F 7.5% 84.4% 42.5Gy/16F 7.4% 84.6%

START A 5.1 yrs 50Gy/25F 3.2% 3.6% 86% 89 % 41.6Gy/13F 3.2% 3.5% 88% 89%

START B 6.0 yrs 50Gy/25F 3.3% 3.3% 86% 89% 40Gy/15F 2.0% 2.2% 89% 92%

Results

Trial Median FU TD/F Cosmesis (good+excellence)

CANADA 5 / 10 y 50/25 79.2 / 71.3 % 42.5/16 77.9 / 69.8 %

START A 5 y 50/25 59.0 % 41.6/ 13 58.1 %

START B 5y 50/25 58.8% 40/15 64.5 %

The Breast 19 (2010) : 163-167

Result :- Cosmesis

HF –WBRT is an acceptable treatment option for patient with

pT1-2 tumor

p N0 disease

Age > 50 years

Especially for patient who do not receive chemotherapy or do not require tumor bed boost

Patient who do not have plan for breast reconstruction

World Journal of Clinical Oncology 2014 Aug 10;5(3):425-439

ASTRO Guideline

acute skin toxicity :- moist desquamation in 30%-50% of patients

erythema and edema of the irradiated breast

telangiectasia and fibrosis of the skin

effect cosmetic result and QOL

Clin Oncol 2004 ; 16 :12-16 Eur J Cancer 2008 ; 44 : 2587-2599 Radiother Oncol 1994 ;33: 106-112 IJROBP 2007 ; 68 : 1375-1380

With Conventional 2D-RT :-cause

Modern Radiotherapy Techniques Imaging Treatment Planning System New Radiation Machine

Results Improved efficacy Decreased toxicity Faster and convenient treatment

Modern RT techniques (3D-CRT/IMRT)

Advances of computed tomography can now demonstrate

three dimensional tissues/organs

Advances in radiation treatment planning system

Advance in radiation machine

We can now give high radiation doses to the tumor while sparing the normal surrounding tissue

LINAC with MLC

We are moving from 2D-RT to

1. Three-dimension RT (3D-CRT)

2. Intensity Modulated RT (IMRT)

IMRT has been shown to improve homogeneity and reduce acute toxicity with improve QOL

CO 2008 ,May 1 : 28 (13):2085; 2085-2072

New RT techniques

2D-Tangential beams 3D-CRT/IMRT

High exposure dose to lung and heart and also hot spot at periphery area

More precise beam to targetwith dose homogeneity

LUNG: V20 = 22% (wedge) = 19% (IMRT)HEART: V5 = 0% (wedge) = 10% (IMRT)

V25 = 0% (wedge) = 0% (IMRT)VOLUME : 2288.09 cc Breast Separation : 29.5 cm

Pt.1

Showed no statistically significant difference in 5- year

Locoregional recurrence 2.56% VS 1.35 % Overall survival 92.5 % VS 91.7 %

JCO 2013 ;31 : 4488-4495

IJROBP 2008 ;72 :1031-1040

Standard Wedge-based tangential fields VS IMRT

Acute reaction Conventional Wedge IMRT

Dermatitis grade >/= 2 85% 41%

Breast edema 28% 1%

Hyperpigmentation 50% 5%

Change in breast appearance 58% 40%

Late toxicity :- no difference in the reported occurrence of reaction pneumonitis, fat necrosis , or second malignancy

IJROBP 2008 ;72 :1031-1040 IJROBP 2007; 68 : 1375-1380 IJROBP 2012 ; 84 : 888-893

Side effects

70%-90% of IBTRs occurred at or in close proximity to the lumpectomy cavity.

APBI may offer equivalent local control to WBRT

NEJM 2002 ; 347 : 1233-1241

NEJM 2002 ; 347 : 1227-1232

Accelerated Partial Breast Irradiation (APBI)

Include

short treatment time :- from 5-6 weeks to 1-2 weeks decreased breast , heart and lung RT volume Possible improved cosmesis reduce cost and waiting time

Potential Disadvantage :- the possibility that occult foci of cancer exist elsewhere in the breast and will not be treated.

Ann Surg Oncol 2012 ;19 : 3275-3281

Potential advantages of APBI

Brachytherapy : - Interstitial brachytherapy - Intracavitary brachytherapy - Intraoperative radiation

External beam RT : - 3DCRT - IMRT/VMAT

Ongoing trial : - NSABP B-39 RTOG 0413 - WBRT VS APBI

Modalities for APBI

Partial Breast Irradiation (PBI)

ImplantationMammosite

(3D-CRT / IMRT)

Intrabeam

Patients :- Quadrantectomy , age >/= 48 years

- IDC , T </= 2.5 cm Lancet Oncol 2013;14:1269-1277 - Node negative BreastCancer Res treat 2010;124:141-151

Treatment : ARM I :- WBRT 50Gy/25F , +/- 10 Gy boost ARM II :- IORT 21 Gy x 1 F ( electron up to 9 MeV)

Results : - median FU 5.8 y WBRT IORT -IBTR 4 pts 35 pts p=0.0001

- 5-y OS 96.95% 96.8% p=0.59

ELIOT trial 1,305 patients

Patients : - Lumpectomy , age >/= 45 years - IDC , node negative

Treatment :-ARM I :- WBRT 40-56 Gy +/- Boost 10-16 Gy VSARM II :- IORT single dose 20 Gy ( low –energy X-ray 50 KV)

TARGIT – A trial 3,451 pts

Results : TARGIT –A

results WBRT IORT

4-y LR 0.95% 1.2 % p=0.4 5-y LR 1.3 % 3.3 % p=0.042 Breast cancer death 1.9 % 2.6 % p= 0.56 Non-breast cancer death 3.5% 1.41% The overall mortality was similar Major toxicity 3.3% 3.9 % P = 0.44

14% of patient received WBRT in addition to IORT according to the final pathological report.

Lancet 2010 ; 376 ; 91-102 Lancet 2014 ; 383 ; 603-613

Currently, standard of care after conserving breast surgery is still whole breast irradiation.

APBI :- awaiting the prospective setting (RTOG 0413/NSABP B-39)

Summary

B-39/0413 Protocol DesignEligible patient treated with

lumpectomy

StratificationDisease stage-DCIS, invasive N0, invasive N1(1-3)

Age ≤ 49, ≥ 50Hormone receptor status (ER-,ER+)

Randomization

WBI50-50.4 Gy in 1.8-2.0 Gy fractions to whole breast,

followed by electron boost to surgical bed with margin for

total dose of 60-66.6 Gy

APBI34 Gy in 3.4 Gy bid x 5-7 days

Interstitial BrachytherapyOr

34 Gy in 3.4 Gy bid x 5-7 days Mammosite Balloon Catheter

Or38.5 Gy in 3.85 Gy bid x 5-6 days

3D Conformal External Beam

VS

WBRT 50 Gy/ 25 F VS HF 6 Gy x 5 F once weekly HF 5.7 Gy x 5 F once weekly The preliminary results showed inferior outcome for HF regimen

Radiother Oncol 2011 ; 93- 100 Semin Radiat Oncol 2008;18:257-264 Semin Radiat Oncol 2008 ;18:215-222

Ongoing Trial-UK FAST trial

Proton Beam Therapy VS IMRT for Breast Radiation

MDACC

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