New techniques in breast radiotherapy

NEW TECHNIQUES IN BREAST RADIOTHERAPY
HELLENIC SCHOOL OF MASTOLOGY:
17-18 SEPTEMBER2010,
ATHENS
XENOPHON VAKALIS
RADIATION ONCOLOGIST
MEDICAL CENTER OF ATHENS
&
401 MILITARY HOSPITAL OF ATHENS

Historical Perspective
Interstitial Radium Brachytherapy for Breast Cancer, 1917
Radiotherapy for Breast Cancer, London Hospital, c. 1917

Prospective Randomized Trials of Lumpectomy +/- Radiotherapy

Radiation Therapy for Early Stage Breast Cancer Following Lumpectomy
Whole Breast Irradiation
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 + margin
1.8 – 2 Gy fraction given 5 days/ week
5 – 7 week total treatment duration

Breast Irradiation Technique
External Beam
Treats “whole breast”
Large volume of incidental tissues
Requires protracted (6—7 week) delivery

Image-based Conformal Radiation Therapy:
60 Gy
62 Gy
50 Gy
20 Gy
45 Gy
axial
sagittal
Left Breast

Accelerated Whole Breast Irradiation:Reducing the burden of care
Canadian Phase III Randomized Trial:
42.5 Gy – 16 fractions – 22 days vs.
50 Gy – 25 fractions – 35 days
1,234 patients - T1 – T2, N 0 (80% T1)- ER positive - 71% - Median F/U: 69 months

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 RTAwaiting 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

Cured from
Breast Cancer
Died of Cardiac
Toxicity
Adapted from Larry Marks, Duke

Overall survival: radical mastectomy + / - RT
First 10 years
Next 25 years
Cuzick et al: Recent Results Cancer Research 111:108-129, 1988

XRT worse
XRT better
XRT better
XRT worse
XRT better
XRT worse
Overall Survival
Cardiac Mortality
Breast 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
Prone and IMRT
Lateral Decubitus
Campana et al 2005
DeWyngaert et al 2007

Radiation techniques
Active Breathing Control + IMRT
Breath hold in deep inspiration
Remouchamps et al 2003
Lu et al et al 2000

Cardiac Sparing
V5 Volume receiving 5% of the dose

Heart Block Examples
Midline
Heart Block
Recent Patient
Marks IJROBP 1994.
Marks et al

Late cardiac morbidity(EBCTCG,Lancet 2000;355:1757-1770)
field
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
Breast
contour
Heart
contour
Maximum Heart Distance (MHD)

Prone Breast RT

Goodman
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.

3-DCRT for left prone breast radiation:
Improved targeting and avoidance of lung
Sagittal
45 Gy
60 Gy
Lumpectomy
50 Gy
PTV
Transaxial

Pattern of In-Breast Cancer Recurrences Following Breast Conserving Therapy
The majority of cancer recurrences in the treated breast occur at the lumpectomy site

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
Intracavitarybrachytherapy with Mammosite
Intraoperative electron beam therapy
3D conformal radiation therapy
Proton beam

Partial breast irradiation techniques

Three Established Methods For PBI
Mammosite®
Multi Catheter
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

Breast Appearance Following Multi-catheter Brachytherapy
5 years post treatment

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
61 mo.
5%
89%
61 y
1.4 cm
17.5%
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 PBI
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

5th Int. Meeting ISIORT Madrid, June 2008
GTV
PTV
Skin
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

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 MammositeBrachytherapy
Isodose Lines
50%
80%
100%
120%
140%
200%
Mammosite® balloon

Prescription Dose
34 Gy
10 fractions over 5 -7days
3-Dimensional rendering of applicator surface and prescription dose cloud.

Day 2 on treatment

2 weeks post treatment

4 months after PBI

Breast Appearance after MammoSite®
3 years post treatment

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

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 ….
Contura
ClearPath™
SAVI

PBI: 3D-CRT Target definition

PBI: 3D-CRT Beam Arrangement
3.85 Gy BID x 10 fractions

PBI: 3D-CRT Isodose Distribution
3850 3752 3655 3557 3460
axial
sagittal
coronal

3-DCRT PBI
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.

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
NSABP B-39/RTOG 0413 TrialPhase III

Endpoints
Primary: in-breast tumor recurrence
Secondary:
Distant disease-free survival
Overall survival
QOL: Cosmesis, fatigue, symptoms, burden of care

ZeissIntrabeam®
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

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, BC
Presented 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

Goodman
Figure 4a. Transverse Dose Distributions
IMRT
Conventional
Isodose
in %
113
108
100
90
50
102
10

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
Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views
Photon
Photon
Proton
Proton
Isodose lines
— 103%
— 100%
— 75%
— 50%
— 25%

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

IMRT
Protons
Photons
El Ghamry et. Al. IJROBP 2002

Dose to Heart

Dose to Lung

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 $10.6K
3D-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

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