New techniques in breast radiotherapy

NEW TECHNIQUES IN BREAST RADIOTHERAPY

XENOPHON VAKALISRADIATION ONCOLOGIST

MEDICAL CENTER OF ATHENS&

401 MILITARY HOSPITAL OF ATHENS

HELLENIC SCHOOL OF MASTOLOGY: 17-18 SEPTEMBER 2010, ATHENS

http://breastcancer.about.com/library/weekly/aa112700b.htm

Historical Perspective

Interstitial Radium Brachytherapy for Breast Cancer, 1917

Radiotherapy for Breast Cancer, London Hospital, c. 1917

Prospective Randomized Trials of Lumpectomy +/- Radiotherapy

Trial Pt # TumorSize-cm

Surgery % Failure - RT

% Failure + RT

NSABP 1265 <4.0 WE 36 12

Milan 601 <2.5 Q 24 6

Radiation Therapy for Early Stage Breast Cancer Following Lumpectomy

Rationale: Addition of whole breast irradiation following lumpectomy yields local control rates comparable to mastectomy

Treatment: Whole breast irradiation 45-50 Gy to the entire breast 60 Gy to the lumpectomy cavity + margin1.8 – 2 Gy fraction given 5 days/ week5 – 7 week total treatment duration

Whole Breast Irradiation

External Beam

Treats “whole breast”

Large volume of incidental tissues

Requires protracted (6—7 week) delivery

Breast Irradiation Technique

Image-based Conformal Radiation Therapy:

Left Breast

60 Gy

62 Gy

50 Gy45 Gy20 Gy

axial sagittal

1,234 patients - T1 – T2, N 0 (80% T1)- ER positive - 71% - Median F/U: 69 months

Accelerated Whole Breast Irradiation:Reducing the burden of careCanadian Phase III Randomized Trial:

42.5 Gy – 16 fractions – 22 days vs.50 Gy – 25 fractions – 35 days

In-Breast Recurrence

(%)

Excellent/ good

Cosmesis (%)

Accelerated WBI

2.8 76.8

Standard WBI 3.2 77.4

Randomized Boost Trials

Accelerated Whole Breast Irradiation:A Phase II clinical trial of a 4 week course of RT for breast cancer using hypo fractionated IMRT with a concomitant boost.

4 week course – 20 treatments– 45 Gy whole breast dose– 56 Gy boost dose

Results:– 16 patients treated– Acute toxicity: Grade I 57%, Grade

II 43%

Regional Nodal RT Awaiting results of two large trials (France and EORTC)

Regional Nodal RT in BCS Ongoing Trials

Axillary Treatment with CS

Full SCLV Field

IM Nodal Radiation Technique

IM Nodal Radiation Technique

Adapted from Larry Marks, Duke

Cuzick et al: Recent Results Cancer Research 111:108-129, 1988

Overall survival: radical mastectomy + / - RT

First 10 years Next 25 years

Overall Survival

XRT better XRT worse



Cardiac MortalityBreast Ca Mortality

Cuzick JCO 12:452, 1994

The shape of the breast and the position of the heart in relation to the chest wall can vary enormously

Decrease cardiac Exposure to RT

Partial Breast Irradiation Decubitus or Prone positions Breath Hold Technique Respiratory gating technique Proton therapy

Patient’s Position

Campana et al 2005 DeWyngaert et al 2007

Prone and IMRTLateral Decubitus

Radiation techniques

Remouchamps et al 2003 Lu et al et al 2000

Breath hold in deep inspiration

Active Breathing Control + IMRT

Cardiac Sparing

Heart V5 V10 V20

Proton 4.1 2.7 1.5

Photon/Electron

33.2 20.8 10.4

PWTF 19.7 12.0 9.5

V5 Volume receiving 5% of the dose

Heart Block Examples

Heart Block

Midline

Marks IJROBP 1994. Recent PatientMarks et al

Late cardiac morbidity (EBCTCG,Lancet 2000;355:1757-1770)

Breast cancer mortality reduced by 13%

Increase in annual mortality rate from other causes by 21%

Increase primarily due to excess deaths from cardiovascular causes

Cardiac effects may not emerge until 15 yrs after treatment

field

Maximum Heart Distance (MHD)

Heartcontour

Breastcontour

Prone Breast RT

Prone Breast RT

Figure 1a. Customized prone breast board with adjustable aperture and wedge for contralateral breast.Figure 1b. Ipsilateral breast and anterior chest wall hang in a dependent fashion away from the thorax while the ipsilateral arm is placed above the head

Goodman

Figure 6. Left breast irradiation using prone breast IMRT technique can spare left ventricle and coronary arteries.

Goodman

Transaxial

Sagittal

3-DCRT for left prone breast radiation:

Improved targeting and avoidance of lung

60 Gy

50 Gy

45 Gy

Lumpectomy

PTV

Elsewhere Failure (Outside Lumpectomy Region)

No XRT XRT Randomized Trials (BCT)

# Cases

Follow-up Interval (mos)

Crude % Crude % Ontario

837 43 15/421 3.5 4/416 0.9

Milan III

579 109 8/280 2.8 2/299 0.6

NSABP B06

1265 144 17/636 2.7 24/629 3.8

Uppsala-Orebro

381 33 3/194 1.5 1/187 0.5

Finland 152 80 4/72 5.5 4/80 5.0

The majority of cancer recurrences in the treated breast occur at the

lumpectomy site

Pattern of In-Breast Cancer Recurrences Following Breast

Conserving Therapy

Potential Benefits of Partial Breast Irradiation

Reduce time and inconvenience of BCT Improve documented underutilization of

breast conserving therapy (BCT)? Potentially reduce acute and chronic

toxicity Reduce burden of care for patients Eliminate scheduling problems with

systemic chemotherapy

Rationale for Partial Breast Irradiation (PBI)

10%-40% of those who are candidates for breast conservation therapy actually do not receive it.

Why?– Patient’s choice– Complex and prolonged treatment course

can be inconvenient for those with poor access to a radiation facility, the elderly and working women

– Physician bias

Techniques for PBI

Interstitial brachytherapy with HDR or LDR

Intracavitary brachytherapy with Mammosite

Intraoperative electron beam therapy

3D conformal radiation therapy Proton beam

Partial breast irradiation techniques

InterstitialBrachyther.

IntracavitaryBrachyther

Intraop.RT

3DConformal RT

Dose 34 Gy in 10 frIn 5 days

34Gy in 10 frIn 5 days

20-21Gy in single fraction

30 Gy in 5 fr. In 10 days

Target 1.5 cm margin around WLEcavity

1cm aroundWLE cavity

Visual by surgeon and radonc perop

2.5cm margin around WLEcavity

Pros Many dwell positions forIrreg. cavity

Ease of placement andplanning

Single doseSpares skin

Fits with standard RTmachines

Cons Operatordependent

High costFewer dwellpositions

RT before path knownSpecialised centres only

Larger fields(respiration) and more normal tissue

Three Established Methods For PBI

Multi CatheterMammosite®

3-D Conformal

Accelerated Partial Breast Irradiation

Treatments delivered twice daily (with treatments separated by six hours) for 10 treatments delivered in 5 treatment days.

Delivery of radiation limited to lumpectomy site with a margin of normal tissue.

Each treatment takes approximately 10 minutes to deliver.

Target definition


Benefits:– Limited radiation exposure to normal

tissue– Treatments completed in one week

instead of six weeks


Limitations:– May require additional surgical

procedure – Requires twice daily treatment– Newer modality with far fewer

patients treated and much shorter follow-up

– As of now, no direct comparison with standard radiation

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

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.

Breast Brachytherapy

Multi-Catheter Brachytherapy

Dose Distribution of MultiCatheter PBI

PTV

100% isodose

5 years post treatment

Breast Appearance Following Multi-catheter Brachytherapy

Patient Selection for Breast Brachytherapy

Patients older than 45 Tumors less than 2 cm. in size >2mm. Margins Preferably Infiltrating Ductal or loclized

low grade DCIS. No Lobular CA There must be at least 7mm. of tissue

between the catheter surface and the skin of the breast.

Advantages of Breast Brachytherapy vs. External Beam RT

6 weeks (30 fractions) Homogeneous dose Logistical problem for

patients Difficult for frail, elderly,

or chronically ill patients Interferes with schedule

of working women Some BCT candidates will

opt for mastectomy

5 days (10 fractions) Dose is higher to tissue

at greatest risk for sub-clinical malignant cells

Reduction in skin, cardiac and lung dose

Ideal for patients who live far from RT Center

Convenient May increase number

of women treated with BCT

Disadvantages of Breast Brachytherapy vs. External Beam RT

Noninvasive Can cover nodal regions Treats multi-centric

carcinoma Low complication rate Linear accelerators

widely available Most radiation

oncologists experienced

Invasive Not useful for treatment

of nodal basins May miss tumor foci in

other quadrants Low, but definite risk of

infection and/or fat necrosis

Requires special skills for performing; in placing catheters and dosimetry

MultiCatheter PBI: HDR/ LDR

Institution

Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Tam%

LR%

Exc/ good

Cosmesis%

Oschner 51 63 75 1.4 18 - - 2 -

Beaumont 199 65 65 1.1 12 - 57 1.2 99

Tufts-NEMC 32 63 33 1.3 9 79 61 3 88

VCU 44 62 42 1.2 18 - 66 0 80

Nat. Inst. Onc.

Budapest45 56 81 1.2 2 82 16 6.7 97

Guys Cs 137 49 58 75 2.5 46 - - 18 81

61 mo. 5% 89%61 y 1.4 cm17.5%Average:

Breast Brachytherapy

There has got to be a better way than all of those needles.

Mammosite device from Proxima Therapeutics may be the answer.

FDA approved the device in May 2002

Mammosite® Breast Brachytherapy Applicator

• Simplified brachytherapy method for PBI

• Dual lumen single catheter with expandable balloon at

end• Balloon expands to fill the

lumpectomy cavity• Radiation dose prescribed

to 1 cm beyond balloon surface

• Uses 192Ir (HDR) as the source

• FDA approval May 2002

MammoSite PBI

5th Int. Meeting ISIORT Madrid, June 2008

Volume Definition

PTV: GTV + 1.5 – 2.0 (clinical margin) + 0.5 (setup margin)

excluding skin and chest wall

Skin: 5 mm depth below skin surface

GTVPTVSkin

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.

CT Planning for Mammosite Brachytherapy

Isodose Lines

50%

80%

100%

120%

140%

200%

Mammosite® balloon

3-Dimensional rendering of applicator surface and prescription dose cloud.

Prescription Dose

34 Gy 10 fractions

over 5 -7days

Day 2 on treatment

Day 2 on treatment

2 weeks post treatment

4 months after PBI

Breast Appearance after MammoSite®

3 years post treatment

MammoSite PBI

Institution Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Local relapse

%

Exc/ good

Cosmesis%

Initial Multi- Institutional 43 69 48 1.0 0 - 0 80

Rush Univ. 112 64 -88%

Tis-T-17 - 0 80

Tufts-NEMC/ VCU 28 62 19 1.1 0 100 0 86

St. Vincent Hospital 32 62 11 97% T-1 9 94 - 86

Average: 64 y 26 mo 1 cm 4% 0% 83%

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.

Conclusion

The MammoSite RTS is the most commonly used PBI technique

MammoSite is minimally invasive, offers acceptable cosmetic results, and induces mild side effects

The duration of treatment is only five days making it more convenient for patients

The MammoSite RTS has criteria which prevent some patients from eligibility– New devices such as SAVI, ClearPath, and

Contura are overcoming those limitations


… and Mammosite begat ….

SAVI

ClearPath™

Contura

PBI: 3D-CRT Target definition

PBI: 3D-CRT Beam Arrangement

3.85 Gy BID x 10 fractions

PBI: 3D-CRT Isodose Distribution

axialsagittal coronal

3850 3752 3655 3557 3460

3-DCRT PBI

Institution

Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Local relapse

%

Beaumont 92 62 23 - 2 - 0

NYU 78 67.5 28 0.9 0 100 0

MGH 61 6212

(min) 0.9 0 - 0

RTOG 0319

42 61 - 0.85 - - -

Summary: 273 63 21 0.9 < 1 0

Accelerated Partial Breast Irradiation:Summary

Accelerated partial breast irradiation allows patients to complete a course of treatment in one week as opposed to the standard six weeks.

Treatment limited to part of the breast may be associated with less morbidity of treatment and better cosmetic outcome.

Hopefully, the randomized, prospective NSABP trial will answer the question of equivalence of partial and standard breast irradiation.

NSABP B-39/RTOG 0413 TrialPhase III

Stage 0, I-II breast cancer treated by lumpectomy

Randomization

WBI• 50-50.4 Gy (1.8-2.0 Gy)

Fractions to the whole breast followed by boost to 60 -66.6 Gy

PBI• 34 Gy in 3.4 Gy fxs bid

Mammosite® or Multicatheter brachytherapy

OR• 38.5 Gy in 3.85 Gy fxs bid

3D-CRT

Endpoints

Primary: in-breast tumor recurrence

Secondary:– Distant disease-free survival– Overall survival– QOL: Cosmesis, fatigue, symptoms,

burden of care


Zeiss Intrabeam®

-50 kV x-ray source at the end of a 15 cm long, 3.5 mm diameter tube.

-Spherical applicators with diameters of 15-50 mm in steps of 5 mm

-Dose rate of about 2 Gy/min at 1 cm in water

Spherical applicators 1.5 to 5cm diameter in 0.5cm steps

Uniform surface dose-rate

The pliable breast tissue is wrapped around the applicator. Subcutaneous stitches aid conformation, while ensuring that the skin is at least 1cm from the

applicator surface.

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.

Trials of partial breast RT

Trial Target accrual RT Technique Duration of RT

NSABP B-39 9000 Multisource Ir-192

5 days

TARGIT 3000 IntraoperativeXrays

1 day

ELIOT 2000 Intraoperativeelectrons

1 day

IMPORT Low 2000 External beamIMRT

3 weeks

GEC-ESTRO 1170 Multisource Ir-192HDR/PDR

2.5-4 days

Intensity Modulated Radiation Therapy (IMRT)

Dose distribution to breast with standard tangential fields

Dose distribution to breast using IMRT


IMRT for Early Breast


Phase III Randomized Study of Intensity Modulated Radiation Therapy Versus Standard Wedging Technique for Adjuvant Breast Radiotherapy

J. Pignol, et. al.Toronto, ON and Victoria, BCPresented ASTRO 2006, Plenary Session

Tangential Fields vs IMRT

358 patients randomized to standard breast irradiation or IMRT

Dose of up to 50 Gy + 16 Gy boost Endpoints of acute skin reaction and

incidence of moist desquamation

Tangential Fields vs IMRT

311 Patients included in analysis Decreased moist desquamation with

IMRT- 31% vs 48% (p=0.0019) Decreased moist desquamation in

inframammary fold with IMRT- 26% vs 43% (p=0.0012)

IMRT lowers the dose of radiation to the lung and to the heart (in patients with left sided breast cancers).

Moist Desquamation

Intensity Modulated Radiation Therapy (IMRT)- Summary

We would not expect to see any differences in terms of recurrence or survival with IMRT

We would hope to see improvement in side effect profile

It may take years or decades to document a benefit in terms of cardiac toxicity

IMRT Conventional

Figure 4a. Transverse Dose Distributions

113 108 100 90 50Isodose in % 102 10

Goodman

DVH – Coronary artery region

Other Clinical Scenarios

Inoperable presentations Bulky, non-resectable recurrent cancer IMRT plans have sometimes looked

significantly better than 3D conformal, on a CASE BY CASE basis


Proton/Photon Comparison

Photon

Proton

Photon

Proton


Conclusions from Proton Therapy Study

- Protons spare non target breast tissue - reduction of 40%-45% vs. mixed modality

- Protons also spare contralateral lung & heart

- May permit retreat for pts with ipsilateral recurrence outside original field.

- Dose escalation?- Effect of neutrons in passively scattered

proton beams (Hall et. al.), but not in IMPT


DVH for non-target breast tissue

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

Dose(%)

Vol

ume(

%) Proton

IMRT

XRT

IMRT Protons Photons

El Ghamry et. Al. IJROBP 2002


Dose to Heart

Photons/Electrons Protons p-value Max dose (Gy) 3.2 0.8 0.001 Min dose (Gy) 0.2 0.01 .0001 D20 (Gy) 0.4 0.0 0.0001 D10 (Gy) 0.6 0.0 0.0001 D5 (Gy) 0.9 0.0 0.001


Dose to Lung

Photons/Electrons Protons p-value Max dose (Gy) 28 19 0.001 Min dose (Gy) 100 0.4 .001 D20 (Gy) 1.3 0.0 0.001 D10 (Gy) 2.5 0.4 0.0001 D5 (Gy) 4.1 2.1 0.005


Cost vs. Benefit: Protons vs. Photons

Benefit: Volume of non-target breast tissue receiving 50% of the prescribed dose is reduced 40% to 45%

Cost: WBI+B $10.6K3D-CPBI proton $13.2K

(+25%)3D-CPBI-photon $5.3K (-

50%) A. Taghian et. al. IJROBP. 65:1404-1410; 2006

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New techniques in breast radiotherapy