Partial Breast Irradiation

Carol Marquez, M.D.Associate Professor,

Department of Radiation MedicineOregon Health and Sciences

University

Goals of discussion Discuss the changing epidemiology of breast

cancer Present the data supporting breast

preservation therapy (BPT) Discuss the rationale for partial breast

irradiation (PBI) Show the techniques and difficulties with PBI

Breast Cancer StatisticsThe good news: Mortality declined by 2% per year from 1990 to 2001, with the greatest declines in women younger than 50 years. Estimated deaths in 2007 = 40,910.The bad news: An estimated 180,510 new cases will be diagnosed in 2007. The incidence has continued to gradually increase since 1990. Recent decline in ER + breast cancer incidence may be secondary to 40% decline in use of hormone replacement therapy between 2000- 2003.

SEER Age-Adjusted Incidence Rate ComparisonFor Breast CancerSEER 9 Registries for 1975-2004

Stage at presentation is declining The increase in incidence from 1980-87 was largely

due to increased use of screening mammography. During that time, the incidence rates of tumors <2

cm more than doubled while the rates of tumors >3 cm decreased by 27%.

The incidence rates of DCIS has increased more than sevenfold from 1980-2001.

Breast cancer is still a disease of older women

Current age Risk of breast cancer in next 10 years

Or 1 in:

20 0.05% 1,98530 0.44% 22940 1.46% 6850 2.73% 3760 3.82% 2670 4.14% 24Lifetime 13.22% 8

Who is eligible for breast preservation therapy? Classically the size cutoff was 4 cm but recent consensus

conference stated that any size is eligible as long as clear margins are obtained with an acceptable cosmetic result; NCCN states that tumors > 5 cm are a “relative” contraindication to BPT.

If multicentric tumors can be excised in a single specimen with clear margins (including in situ disease) and the imaging shows no other suspicious lesions, the patient is still a candidate.

No absolute age cutoff; NCCN 2008 guidelines states that women < 35 years have a relative contraindication.

Prior chest XRT and pregnancy are absolute contraindications while active connective tissue disease, especially lupus and scleroderma are relative contraindications.

Where are we in 2008? Majority (~ 85%) of women who present with breast

cancer are eligible for breast preservation therapy (BPT). Survey by American College of Surgeons of 16,643 pts

treated in 1994 shows that 43% of St I/II pts treated with BPT.

Only 86% of women treated with preserving surgery received XRT.

Women don’t receive their XRT after preserving surgery because of age, distance, payer, race and type of hospital (academic vs community).

Who doesn’t need XRT? Four randomized trials comparing

lumpectomy to lumpectomy + XRT. All trials showed an improvement in local

control with addition of XRT. All trials showed no difference in overall

survival between two arms. Trials had varied in terms of surgery and

tumor size allowed.

Features of four trials

Trial N F/U (yrs)

Tumor size

Margins (cm)

Chemo

NSABP-06 1256 20 < 4 cm 0 +

Uppsala 381 5 < 2 cm 2 -

Ontario 837 5 < 4 cm 0.5-1 -

Milan 394 <4 < 2.5 cm NA +

Results of four trialsIBTRno XRT

IBTR+ XRT

Survival no XRT

Survival + XRT

NSABP-06 39.2 14.3 46 47

Uppsala 18 2 90 91

Ontario 29 7 85 87

Milan 9 <1 NA NA

IBTR= In breast tumor recurrence

What can you conclude from these trials? Margins and tumor size do matter even in the face

of radiation; a 2cm tumor treated with good surgical margins has approximately a 20% recurrence rate without XRT not 40%.

Longer f/u is necessary to evaluate the recurrences after XRT.

Radiation does work and does not have a deleterious impact on overall survival.

NSABP B-06: Landmark study 1851 women included

in analysis Mean follow up is 20

years First results published

in 1985 Most recent update

published in 2002

IBTR after 20 years Risk of recurrence

without XRT is 40%. Risk of recurrence with

XRT is 14%. Most of the early

recurrences are near the original primary tumor.

Disease-free Survival (Panel A), Distant-Disease-free Survival (Panel B), and Overall Survival (Panel C) among 589 Women Treated with Total Mastectomy, 634 Treated with Lumpectomy

Alone, and 628 Treated with Lumpectomy plus Irradiation

Fisher, B. et al. N Engl J Med 2002;347:1233-1241

What else did we learn from NSABP-06? Addition of chemotherapy does not eliminate the

need for XRT but does improve the local control in those receiving XRT; chemo + no XRT, IBTR = 44% vs. chemo + XRT, IBTR= 9% (no chemo + XRT, IBTR= 14%).

Recurrences after XRT may occur later than if no XRT is given; no XRT, 73% of recurrences occurred in the 1st 5 yrs while with XRT, 40% of recurrences occurred in the 1st 5 yrs.

What else can be done instead of whole breast irradiation? Hormonal therapy Selection of patients Minimizing treatment volume

What about hormonal therapy? NSABP-21 enrolled pts with ER/PR + tumors, < 1cm

in size with – margins, and node negative. Randomized pts to XRT, tamoxifen, or XRT +

tamoxifen. Found that XRT was still warranted in this select

group; at 8 yrs, IBTR with Tam = 16%, with XRT= 9%, with XRT + Tam = 3%.

Recent articles on avoiding XRT in older women Two recent (2004) articles examined the use of

Tamoxifen only after surgery in select older women to avoid radiation.

The overall survival was equal in both arms. The local recurrence was low without radiation, especially in those over 70 with ER+ tumors.

Those receiving XRT had a lower rate of recurrence (4-7% vs. 0-1%). They also reported more breast pain.

Why partial breast irradiation (PBI)? Rationale is that by having a therapy that can be

completed in a short period of time (e.g. 1 week) more patients can be eligible for BPT.

Majority of recurrences seen in those pts not receiving XRT occur at or near tumor bed so rest of breast may not need treatment.

Treating less of the breast may produce fewer side effects, specifically pain and fatigue.

How is PBI performed? Several methods now available including

brachytherapy, 3D conformal, IORT, protons. Initial experience was with interstitial

brachytherapy, either HDR or LDR. Target volume is the tumor cavity plus 1 cm. Treatment is given in twice daily treatments

of 3.4 Gy per treatment.

Single Institution results with PBI

Institution N F/U (mos)

IBTR Cosmesis

Ochsner (HDR) 26 20 1 75

Ontario (HDR) 39 20 2.6 NA

Ochsner (LDR) 26 20 1 78

Beaumont (LDR) 120 82 1 91

Beaumont (XRT) 22 20 0 100

Techniques for PBI Interstitial brachytherapy with HDR or LDR Intracavitary brachytherapy with Mammosite Intraoperative electron beam therapy 3D conformal radiation therapy Proton beam

Interstitial brachytherapy Catheters are placed

intraoperatively or later; usually 2 planes

Typical doses with HDR = 30-36 Gy and LDR = 45-60 Gy

Treatment delivered over one week.

Difficulties with interstitial brachytherapy Very user dependent, especially on number

of cases performed. Certain toxicities increase over time

(telangiectasias and fat necrosis) while others stabilize (breast pain, breast edema).

Cosmetic results appear to improve over time.

Features of Hungarian Trial Randomized women to whole breast (50 Gy, no

boost) vs. PBI; n=258 women with median f/u of 66 months.

For PBI, 69% delivered with HDR interstitial, 5.2 Gy x 7 bid over 4 days. For the others, electron beam used, 50 Gy in 2 Gy fractions.

No lobular carcinoma included; 96% had margins > 2 mm, 95% were < 2 cm, and 94% were node negative.

In the PBI arm, 63% were grade 1 while in whole breast, 50% were grade 1.

Results of Hungarian TrialWBI (%) PBI (%)

IBTR- marginal 1.5 2.3

IBTR-elsewhere 1.5 2.3

Excellent-good cosmesis

65% photons; 52% cobalt

81% HDR; 70% EB

Fair-poor cosmesis 24% photons; 48% cobalt

19% HDR; 30% EB

Grade 2-4 Fat necrosis

9% 10% HDR; 8% EB

MammoSite brachytherapy Balloon is placed into

surgical cavity. Balloon available in

spherical and elliptical shapes.

Balloon sizes are 4-5 cm.

Ten fractions given in 5 days, 34 Gy.

Difficulties with Mammosite Balloon must conform to

cavity shape without air gaps. Device explanted in ~ 10-15% of pts.

Ideal is to have 7 mm b/w balloon and skin to decrease risk of erythema.

Very dependent on surgical placement.

“Long” term results with Mammosite Three year results from the American Society

of Breast Surgeons registry trial showed a IBTR 2 year actuarial rate of 1.04% with good to excellent cosmetic results were seen in 93% of patients (n=67).

William Beaumont experience showed 2.9% 3 year actuarial rate of IBTR with good to excellent cosmetic results in 88% of patients at 36 months.

Toxicities of Mammosite Seroma formation: Risk is increased with

open technique for placement. In Beaumont series, found 60% risk with open cavity vs. 30% in closed cavity; overall rate of 45%, with 10% symptomatic.

Fat necrosis: Risk may be slightly lower than with HDR and no difference with placement technique.

3D Conformal PBI Surgical clips (6) are placed at the time of

lumpectomy. The clips define the excision cavity which is

expanded by 15 mm to get the CTV and 10 mm are added to establish the PTV.

Ten fractions over 5 days giving 38.5 Gy, with 6 hours between treatments.

The good and bad of 3D conformal PBI

Performed on a standard linear accelerator; less invasive.

Requires more time for target delineation and planning; typically plans use 3-5 non-coplanar beams.

Greater concern for dose to heart, lung, and contralateral breast in developing treatment plan.

More issues with breathing motion and setup uncertainties.

Limited results with 3D Conformal Recent update from William Beaumont

Hospital presented interim analysis with median followup of 2 years for 91 patients.

No IBTRs were observed but 2 patients developed distant mets (1 patient was node positive).

Good to excellent cosmesis was seen in 95% of patients, with treatment related toxicities stabilizing by 3 years post treatment.

Proton beam for PBI Early experience from MGH

in 20 women showed acceptable cosmetic results with increase skin toxicity as compared to photons.

Dose modified to 32 CGE given the increased RBE of protons; 8 fractions delivered over 4 days.

Intraoperative Radiation Therapy (IORT) for PBI TARGIT trial is comparing whole breast

irradiation to IORT delivering a single dose of 20 Gy. Primary accrual is in Europe.

Using the Intrabeam Photon Radiosurgery System, 50 kV x-rays.

Trial has enrolled 900 patients with target of 2200 patients.

Problems with IORT with Intrabeam Margin status: with

delivery of treatment at the time of lumpectomy, may have persistent positive margins found.

Depth of penetration: limited coverage with dose distribution. Patient must have complete excision.

Who is eligible for PBI?(Off study) Tumors < 3 cm Negative margins (> 2mm) Node negative Invasive ductal carcinoma or DCIS Older women (>45 yrs)

Revised Consensus Statement for Accelerated Partial Breast Irradiation, 12/8/05

Randomized trial of whole breast vs. partial breast (NSABP B-39/ RTOG 0413)

Will accrue 3000 patients to 2 arms: Whole breast irradiation (standard) vs. Partial breast irradiation. Three techniques are allowed: Mammosite, interstitial brachytherapy, and 3D conformal.

Patients must have tumor < 3 cm, < 3 positive nodes and tumor may be DCIS or invasive ductal carcinoma.

Patients will be stratified on basis of stage, menopausal status, hormone receptor status, and intent to receive chemotherapy.

Endpoints of the study are local control and cosmesis.

Anticipated problems with NSABP B-39 While most of the single institution experience is

with brachytherapy, most of the patients are treated with 3D conformal.

The study did not allow for planning with IMRT. The cosmetic follow up will be short and may need

to wait at least 5 years before we have adequate information.

Just to make it confusing…. Update from the Canadian accelerated whole breast

trial: Randomized women with negative margins and nodes to 42.5 Gy in 16 fractions or 50 Gy in 25 fractions. Patients with breast separation > 25 cm excluded.

1234 women have been followed for median of 69 months. No difference in local recurrence, overall survival or cosmetic outcome.

10 year local recurrence =6% 10 year good/excellent cosmesis = 70%. Cosmetic

results declined between 3-10 years.

Where will be in 2012? We should have results of

B-39 re: local failure and complications of techniques.

We will continue to refine selection criteria for patients that do not need XRT or who can be treated with PBI.

More patients will be treated with advanced planning, e.g. IMRT.