Accelerated partial breast irradiation

ACCELERATED PARTIAL BREAST
IRRADIATION
Dr. Himanshu Shekhar Mekap
MD, Radiation oncology

INTRODUCTION
• Radiation therapy has an important role in ensuring local control for
patients with early-stage breast cancer who are treated with breast-
conserving surgery.
• Fisher et al. 2002a; Veronesi et al. 2001; Vinh-Hung and Verschraegen
2004). On the basis of the results of these phase III trials, whole-breast
irradiation became a standard component of breast-conservation therapy.
• two randomized trials investigated whether the addition of a tumor-bed
boost following whole-breast irradiation offered further benefit (Bartelink
et al. 2002; Romestaing et al. 1997). Both of these studies demonstrated a
small but statistically significant reduction in ipsilateral breast tumor
recurrence.
Optimal radiation treatment schedule should include 5 weeks of daily
therapy directed to the ipsilateral breast followed by 1 to 1.5 weeks of
Boost directed to the tumor-bed region.

PROSPECTIVE RANDOMISED TRIALS OF LUMPECTOMY WITH/WITHOUT RT

Downsides of Radiation therapy
• Relatively complex Radiation treatment
procedure.
• Expensive treatment -require physical
resources, personnel resources,
• Long Duration of treatment
• life-style disruptions- temporary relocation,
financial burdens, separating patients from
their family & friends
• Distance from a patient’s home to the nearest
radiation facility
• shortage of radiation treatment facilities.
Athas et al, have found an inverse relationship
between the use of breast-conservation
therapy and the distance from a patient’s
home to the nearest radiation facility.
the regions of the country with the lowest
density of radiation treatment facilities have
the lowest rates of breast-conserving
treatments (Farrow et al. 1992)
approximately 20% of patients with early-stage
invasive breast cancer treated in the
United States do not receive radiation as a
component of BCT (Nattinger et al. 2000).

RATIONALE OF APBI in post BCS
• It has been seen that 90% of
relapses in the breast cancer
resides at or near the lumpectomy
cavity itself or in the index quadrant
only.
• Pathological studies from
mastectomy specimen have
demonstrated a lower probability of
subclinical microscopic disease with
increasing distance from primary
tumor.
5
Of the 30% of patients who experience breast
tumor recurrence when radiation therapy is not
delivered, the vast majority (approximately 80%)
will have the recurrence develop at the site of the
original disease (Clark et al. 1992; Liljegren et al.
1999; Veronesi et al. 2001).
In addition, the absolute percentage of recurrences
that develop in a location far away from the tumor
bed is low, ranging from 3% to 5% (Clark et al.
1992; Liljegren et al. 1999; Veronesi et al. 2001).
From these data, many researchers have
hypothesized that treatment directed solely to the
site of the primary tumor may be adequate
This rationale, along with the clinical desire to shorten the radiation course, led to the
investigation of accelerated partial breast irradiation (APBI).

Who is a Candidate for Accelerated Partial
Breast Irradiation?

PATIENT SELECTION CRITERIA FOR APBI

Accelerated Partial Breast Irradiation Consensus Statement From the
American Society for Radiation Oncology (ASTRO)
Patient factors
Age ≥60 y
BRCA1/2 mutation Not present
Pathologic factors
Tumor size ≤2 cm
T stage T1
Margins Negative by at least 2 mm
Grade Any
LVSI No†
ER status Positive
Multicentricity Unicentric only
Multifocality Clinically unifocal with total
size ≤2.0 cm‡
Histology Invasive ductal or other
favorable subtypes
Pure DCIS Not allowed
EIC Not allowed
Associated LCIS Allowed
Nodal factors
N stage pN0 (i
-
, i
+
)
Nodal surgery SN Bx or ALND‖
Treatment factors
Neoadjuvant therapy Not allowed
“suitable” for APBI if all
criteria are present

“Cautionary” group
( Any of these criteria should invoke caution and concern
when considering APBI)
Patient factors
Age 50–59 y
Pathologic factors
Tumor size 2.1–3.0 cm
T stage T0 or T2
Margins Close (<2 mm)
LVSI Limited/focal
ER status Negative†
Multifocality Clinically unifocal with total size 2.1–3.0 cm‡
Histology Invasive lobular
Pure DCIS ≤3 cm
EIC ≤3 cm

Patients “unsuitable” for APBI outside of a
clinical trial if any of these criteria are present
Pathologic factors
Tumor size >3 cm
T stage T3-4
Margins Positive
LVSI Extensive
Multicentricity Present
Multifocality If microscopically
multifocal >3 cm in total
size or if clinically
multifocal
Pure DCIS If >3 cm in size
EIC If >3 cm in size
Patient factors
Age <50 y
BRCA1/2 mutation Present
Nodal factors
N stage pN1, pN2, pN3
Nodal surgery None performed
Treatment factors
Neoadjuvant therapy If used

UPDATED ASTRO GUIDELINES (2016)
[ Patients suitable for APBI ]
1. Age: 50 Years or Older
2. Histopathology : Invasive Ductal Carcinoma.
3. Tumour Size : T1 (Less than or equal to 2cm)
4. Negative margins: (More than or equal to 2mm)
5. NO LVSI
6. ER +ve.
7. BRCA 1 & 2 Negative.
8. DCIS Status: LOW RISK DCIS according to
RTOG 9804.*
*LOW RISK DCIS:
IF it fulfills following
criteria:-
--screen-detected
disease,
--low to intermediate
nuclear grade,
--tumor size ≤ 2.5 cm and
surgical resection margins
negative at ≥3mm.

APBI treatment modalities
Interstitial brachytherapy
– Low dose-rate
– High dose-rate
Intracavitary therapy
– Orthovoltage photons
– Intraoperative electrons
– Brachytherapy
– Ham applicator
External beam therapy
– 3D conformal photons/mixed beam
– Intensity-modulated radiation therapy
– Protons

Whole Breast Reference Volume
(WBRV)
 WBRV has been defined as
that tissue, excluding lung,
which would be irradiated
using normal tangential
external beams.

Whole Breast Reference Volume
Difficult to delineate the extent of actual breast tissue on CT.
Attempt to standardize and automate process for study purpose.
Defined identically for all modalities except Mammosite, in which the
volume occupied by the applicator is excluded.
Needed for:
Initial eligibility assessment
Cavity volume <35% of WBRV
QA/normal tissue dose limitations
<60% of WBRV to receive ≥50% of prescribed dose

Multicatheter interstitial brachytherapy
free-hand or template-
guided approach.
• This technique was initially developed to provide
boost radiation after whole breast radiation
therapy.
• Flexible after-loading catheters are placed
through the breast tissues surrounding the
lumpectomy.
• The catheters are inserted at 1 to 1.5 cm intervals
in several planes -LDR
-HDR

NEEDLES INSERTION
CATHETERS REPLACING
NEEDLES
CATHETER IN-SITU

MulticatheterBrachytherapy
• Dose :3.4 Gy bid x 5 days –34 Gy
Normal tissue :<60% of the whole breast reference volume
should receive ≥50% of the prescribed dose.
Dose volume analysis of target will confirm that ≥90% of the
prescribed dose is covering ≥90% of the PTV_EVAL.
• Dose Homogeneity:
Volume of tissue receiving:
• 150% (V150) of the prescribed dose ≤70 cc.
• 200% (V200) of the prescribed dose ≤20 cc.
• Critical normal tissue DVHs within 5%.

Multicatheter
• Advantages-
• – Highly conformal (possibly the most…)
• – Can be used in non-spherical lumpectomy sites
• – Less prone to patient setup variation
• Disadvantages-
• – Invasive
• – Requires specialized equipment (HDR) beyond the usual Linear
Accelerator

• The mammosite catheter consists of a silicone balloon connected to a 15 cm double-lumen
catheter that is 6 mm in diameter.
• The catheter has both a small inflation channel and a channel for the passage of an Ir-192
high dose rate (HDR) brachytherapy source.

MAMMOSITE
• The balloon is inflated with saline solution mixed with a small amount
of contrast material to aid visualization. The balloon is inflated to a
size that would completely fill the lumpectomy cavity.
• An Ir-192 radioactive source, connected to a computer-controlled
HDR remote after-loader, is inserted through the catheter into the
balloon to deliver the prescription radiation dose.
• applicator can be placed into the lumpectomy cavity at the time of
surgery or in a separate procedure after surgery(USG guided).
• Dose:34 Gy over 10 fractions (3.4 Gy per fraction, BID). The
prescription point is 1 cm from the balloon surface with a minimum
of 6 hours between fractions on the same day.

MammoSite Placement-
TIME OF LUMPECTOMY POST LUMPECTOMY USG GUIDED

MAMMOSITE APPLICATOR QUALITY
ASSESSMENT
Implant quality
1.balloon conformance to the
lumpectomy cavity.
2.distance from the surface of
the balloon to the skin
surface.
3.symmetry of the balloon in
relationship to the central
catheter.
1.Minimum balloon-to-skin
distance of 5 mm is required.
(threshold of at least 7 mm).
2.Adequate Conformance- less
than 10% of the PTV is composed
of fluid or air.
3. A symmetric implant in relation
to the source channel is also
essential for adequate dosimetry.

MammoSite multilumen catheter
 The ML balloon is able to shift radiation dosages away from the skin,
potentially reducing unwanted toxicity to the healthy skin, ribs, sternum and
other subcutaneous structures.
 dosimetric goals can be better achieved using the ML MammoSite balloon
when normal structures (skin and ribs) are close to PTV_EVAL with a distance
of <7 mm and rib distance of <1 cm.

MammoSite Brachytherapy
Target Volume Definitions CTV = PTV = PTV_EVAL = 1.0 cm expansion of
cavity (5mm within skin and excludes chest wall)

MammoSite Brachytherapy
• Dose :3.4 Gy bid x 5 days –34 Gy
• Normal tissue : <60% of the WBRV should receive ≥50% of the dose.
• Tissue-balloon conformance: measure trapped air.
• Minimal balloon surface-skin distance – ideally ≥7 mm,
• if 5-7 mm then confirm skin dose <145%.
• Dose Homogeneity:
Volume of tissue receiving:
• 150% (V150) of the prescribed dose ≤50 cc
• 200% (V200) of the prescribed dose ≤10 cc

APBI RESULTS: MAMMOSITE BRACHYTHERAPY SERIES

Axxent Electronic Brachytherapy
• The novel Axxent electronic brachytherapy system (Xoft) is a modified
form of balloon-based brachytherapy.
• similar to the MammoSite system, consists of a balloon catheter that
is inserted into the lumpectomy cavity by means of a percutaneous
approach.
• The wall of the balloon is covered in radiolucent material that is
visible on a plain x-ray film or CT scan.
• The Axxent electronic brachytherapy system is novel in that it uses an
electronic 50 kilo-voltage x-ray source rather than an iridium-192.

Axxent Electronic Brachytherapy

ADVANTAGES OF AXXENT EB System
• a specifically shielded radiation room or an HDR afterloader unit are not
required.
• Since a shielded room is not required for treatment and the electronic
Brachytherapy device is very portable, the number of setting in which the
device can be used increases.
• Another potential contributing factor is the increase in relative biologic
effectiveness related to the lower energy of the photons emitted by the
electronic brachytherapy source, because of the dominance of
photoelectric absorption at low energies.
-received FDA clearance for the treatment of breast cancer in Jan 2006.

CONTURA
• it has multiple lumens for passage
of an Ir-192 HDR source.
• In addition to a central Lumen, the
Contura balloon has four
surrounding channels to
accommodate the HDR source.
• The positions of the surrounding
channels have a fixed 5-mm offset
around the central channel.

Baloon catheter of CONTURA system
• These channels provide additional source positions and thus allow
increased dose flexibility compared with a single-catheter approach.
• This approach has the potential to reduce the dose to normal tissues
(chest wall and skin) and organs at risk such as the heart and lungs.’
• In addition, multiple catheters make it possible to account for
asymmetric balloon implant with respect to the central channel.
• Like the eB catheter, Contura has a port for a vacuum to remove fluid
or air around the lumpectomy cavity.

Hybrid Brachytherapy Devices
Strut Adjusted Volume Implant (SAVI)
• consists of a central strut surrounded by 6, 8
or 10 peripheral struts.The peripheral struts can be
differentially loaded with a HDR source.
• The device is inserted in collapsed
form through a small incision; once placed, it is
then expanded to fit the lumpectomy cavity by
clockwise rotation of a knurled knob at the
proximal end of the expansion device, expanding
the peripheral struts and providing a pressure fit.
• Radio-opaque markers are present
on three of the peripheral struts (number 2, 4 and
6) for identification during the reconstruction
process in treatment planning.
Strut Adjusted Volume Implant (SAVI)

Hybrid Brachytherapy Devices
ClearPath
• This was developed to combine the advantage of
balloon brachytherapy and multicatheter
brachytherapy.
• The CP device contains six outer expandable plastic
tubes to displace the tissue.
• In the center of the expandable tubes is a central
catheter surrounded by six additional catheters that
allow the passage of an HDR Iridium-192 source.
• In contrast to the SAVI device, the radiation source is
not in direct contact with the breast tissue. CP is a
relatively new device and hence no clinical outcome
data have been reported.
ClearPath

External Beam Radiation Therapy (EBRT)
METHODS
3D CRT
IMRT
PROTON BEAMS
1. The most widely used 3D-CRT approach was initially
described by Baglan et al which was adopted by NSABP B-
39/RTOG 0413 Phase III Trial.
1. four to five tangentially positioned non-coplanar Beams. The tumor
bed is defined by the computed tomography visualized seroma
cavity, postoperative changes, and surgical clips, when available.
1. The clinical target volume (CTV) is defined as the tumor bed with a
1.5 cm margin limited by 0.5 cm from the skin and chest wall.
2. The planning tumor volume (PTV) is defined as the CTV with a 1.0 cm
margin.
3. Dose prescribed is 3.85 Gy twice daily (separated by at least 6 hours)
to a total dose of 38.5 Gy delivered within 1 week

3D Conformal External Beam RT
Dose :3.85 Gy bid x 5 days –38.5 Gy
Normal tissue :All to be contoured
–Uninvolved Normal Breast:
Ideally, <60% of the whole breast
reference volume should receive ≥50% of
the prescribed dose
<35% of the whole breast reference
volume should receive the prescribed
dose.
–Contralateral breast:
The contralateral breast reference volume
should receive <3% of the prescribed dose
to any point.
Ipsilateral lung: <15% of the lung can
receive 30% of the prescribed dose.
Contralateral lung:<15% of the lung
can receive 5% of the prescribed dose.
Heart (right-sided lesions): <5% of the
heart should receive 5% of the
prescribed dose.
Heart (left-sided lesions): The vol. of
the heart receiving 5% of the
prescribed dose (V5) will be <40%
Thyroid: maximum point dose of 3%
of the prescribed dose.

ADVANTAGES OF EBRT
• The technique is non-invasive and the patient is not subjected to a
second invasive surgical procedure or anesthesia, thereby reducing
the potential risk of complications.
• The technique has potential for widespread availability since most
radiation therapy centers already perform 3D-CRT for other cancers.
• external beam approach will be easier for radiation oncologists to
adopt than brachytherapy techniques.
• Treatment results with external beam may be more uniform between
radiation oncologists because the outcome depends less on the
experience and operative skills of the person performing the
procedure than for brachytherapy

DISADVANTAGES OF EBRT APBI
• Breathing motion- The target may move during breathing and the
patient may be positioned differently for different fractions.
• To avoid missing the planned target,a large treatment volume is used
which delivers higher doses to normal breast tissue since the PTV
around the lumpectomy cavity is increased to account for breathing
and setup errors.
• The identification and contouring of the lumpectomy cavity is another
issue. the GTV and CTV are generally defined as the contouring of a
seroma within the lumpectomy cavity. However, the delineation of
the seroma could vary among different observers and even among
experienced ones.

Intra-Operative Radiation Therapy Techniques
• Delivery of a single fractional dose of irradiation directly to the tumor
bed during surgery.
transportation of the patient from the
operating theatre to the radiation
therapy unit during surgery.
development of mobile
intraoperative radiation therapy
devices
• INTRABEAM (KV PHOTONS)
• MOBETRON (MV ELECTRONS)
• NOVAC-7 (MV ELECTRONS)

ADVANTAGES OF IORT
• tissues under surgical intervention have a rich vascularization, with
aerobic metabolism, which makes them more sensitive to the action
of the radiation (oxygen effect).
• minimize some potential side effects since skin and the subcutaneous
tissue can be displaced during the IORT to decrease dose to these
structures.
• IORT eliminates the risk of patients not completing the prescribed
course of breast radiotherapy.
• IORT has the potential for accurate dose delivery eliminates the risk
of geographical miss.

INTRABEAM
• miniature, light-weight (1.6 kg) X-ray source
combined with a balanced floor stand with
six degrees of freedom .
• X-ray source has a probe of 10 cm length
and 3.2 mm Diameter .
• Various spherical applicators with a
diameter ranging from 1.5 to 5 cm are
available to match the size of the surgical
cavity .
• placement of “pursestring” sutures within
the breast to hold the pliable breast tissue
against the applicator surface

INTRABEAM
• The X-ray system produces low-energy photons (30-
50 KVp) with a steep dose fall-off in soft-tissue; no
special shielding is therefore required in the room.
• Treatment time lasts for approximately 20 to 45
minutes, depending on the size of the lumpectomy
cavity, the size of the selected applicator, and the
prescribed dose.
• minimal exposure to the staff and patient; rapid
dose fall-off in the tissue around the applicator
guarantees minimal exposure of the surrounding
tissue such as the lung and cardiac tissue

MOBETRON
• mobile electron beam intraoperative
treatment system.
• composed of three separate units: the
control console, the modulator and
the therapy module.
• produces electrons of nominal
energies of 4 MeV, 6 MeV, 9 MeV and
12 MeV with therapeutic ranges up to
4 cm.
• Single dose of 21 Gy is prescribed.

NOVAC-7
• delivers electrons with the use of
a mobile dedicated linear
accelerator.
• its radiating head can be moved
by an articulated arm that can
work in an existing operating
room.
• It delivers electron beams at four
different nominal energies (3, 5, 7
and 9 Mev).

MICK SHIELDED HDR IORT APPLICATOR
 Applicator is similar in design as the H.A.M.
IORT Applicator (Harrison, Anderson, Mick)
 Available in broad range of sizes; 2-10
Channels.
 Adjustable Tungsten Shields provided.
 Sizing Templates are provided with the
system for proper applicator selection
 Compatible with all of today’s Remote
Afterloading Systems.

TARGIT-A trial
• prospective, randomised, non-
inferiority trial, women aged 45
years or older with invasive ductal
breast carcinoma undergoing
breast-conserving surgery were
enrolled from 28 centres.
• Patients were randomly assigned in
a 1:1 ratio to receive targeted
intraoperative radiotherapy(1113)
or whole breast external beam
radiotherapy(1119).
 estimate of local recurrence in the
conserved breast at 4 years was 1.20%
(95% CI 0.53-2.71) in the targeted IORT and
0.95% (0.39-2.31) in the external beam
radiotherapy group.
 The frequency of any complications and
major toxicity was similar in the two groups
(for major toxicity, targeted intraoperative
radiotherapy, 37 [3.3%] of 1113 vs external
beam radiotherapy, 44 [3.9%] of 1119;
p=0.44)

Intraoperative radiotherapy versus external
radiotherapy for early breast cancer (ELIOT): a
randomised controlled equivalence trial
• 1305 patients were randomised (654 to external radiotherapy and
651 to intraoperative radiotherapy) between Nov 2000, and Dec2007.
• The 5-year event rate for IBTR was 4·4% (95% CI 2·7–6·1) in the
intraoperative radiotherapy group and 0·4% (0·0–1·0) in the external
radiotherapy group (hazard ratio 9·3 [95% CI 3·3–26·3]).
• 5-year overall survival was 96·8% (95% CI 95·3–98·3) in the
intraoperative radiotherapy group and 96·9% (95·5–98·3) in the
external radiotherapy group.

 A cohort of 226 patients with low-risk, early stage breast cancer were treated
with BCS followed by a dose of 21 Gy using IOERT was delivered to the tumor
bed, with a margin of 2 cm laterally.
 With a mean follow-up of 46 months (range, 28-63 months), only 1 case of local
recurrence was reported. The observed toxicity was considered acceptable.

LIMITATIONS OF IORT
• absence of final histopathological report at the time of radiotherapy.
• patient's longer stay at the operation theatre under general
anaesthesia.
• Potential risk of late complications related to the administration of
single high-dose radiation.

Randomized trials comparing whole-beast
irradiation with APBI.
NIC,
Hungary
258 5.5 Surgical
clips
(1) Whole-breast RT: 50
Gy in 25 fractions using
either Cobalt-60 (n =29)
or 6–9-MV photons (n =
100)†
3.4%
(4/130)
1.7%
(2/130)
.96% 91.8%
(2) APBI: HDR
interstitial implant to
36.4 Gy in 7 fractions
b.i.d. (n = 88) or
external-beam RT with
electrons to 50 Gy in 25
daily fractions (n =
40).‡PTV defined as
lumpectomy cavity + 2
cm
4.7%
(6/128)
1.6%
(2/128)
.98.3% 94.6%
At 5 y p=
0.50
At 5 y p=
NR
At 5 y p =
NR
At 5 y p =
NR
Trial N
Median
follow-
up (y)
Lumpecto
my cavity
definition Arms IBTR
Tumor
bed
failure CSS OS
Partial breast irradiation using interstitial HDR implants or EBRT to deliver
radiation to the tumor bed alone for a selected group of early-stage breast
cancer patients produces 5-year results similar to those achieved with
conventional WBI.

Yorkshire Breast Cancer Group trial ..
(1) Whole-breast
RT: 40 Gy in 15
fractions
followed by
boost of 15 Gy in
5 fractions
(2) APBI: 55 Gy in
20 fractions using
external-beam
techniques. PTV
not defined
ARMS
WHOLE-
BREAST RT
APBI P VALUE
IBTR 4% 9% 0.07
TUMOR BED
FAILURE
- 8% NR
LRF 9% 24% 0.05
OS 73% 70% 0.75
N=174, MEDIAN=8 Yrs

 April 1993 to December 2001
 199 patients with Stage I–II breast
carcinoma
 breast-conserving therapy with APBI
 low-dose-rate (LDR) or high-dose-rate
(HDR) implant
Peter Y. Chen, M.D. et al,
Department of Radiation Oncology, William
Beaumont Hospital, Royal Oak, Michigan.
 The median follow up was 6.4 years. Breast pain, edema, erythema, and
hyperpigmentation all diminished over time.
 Breast fibrosis and hypopigmentation increased until the 2-year mark and then
stabilized. Fat necrosis and telangiectasia increased over time,
 with a fat necrosis rate of 11% at 5 years
APBI with interstitial brachytherapy resulted in mild chronic toxicities,
the majority of which diminished or reached a plateau over time. Long-term
cosmesis was good to excellent in 95–99% of patients and stabilized at 2 years

Reasons to consider APBI as an
investigational treatment
• There have been no completed phase III trials comparing more
recent APBI approaches to whole-breast treatment.
• The long-term efficacy of APBI with modern techniques remains
unknown.
• The appropriate patient selection criteria for APBI treatment are
unknown.
• The late normal-tissue effects of APBI are unknown.
• one of the limitations to current APBI approaches is the
uncertainty of what constitutes the most appropriate target
volume.

Reasons to consider APBI an acceptable
standard of care for selected patients.
• Mature results from a comparative phase III trial will likely
not be available for a decade.
• Whole-breast irradiation is not an option for some breast
cancer patients because of its protracted treatment
schedule.
• Initial institutional and phase II multicentre trials
investigating APBI have shown excellent local control rates
and low rates of serious normal-tissue injury

CONCLUSIONS
• The interest in APBI is evident from the proliferation of approaches
and devices. However, studies are required, not only to evaluate the
efficacy of APBI, but also to assess the safety and toxicity of the
various techniques and dosing schedules.
• it is hoped that more research will be carried out to determine the
strengths and weaknesses of the different techniques; thereby
creating a consensus and identifying where each technique may be
best applied.
• The acceptance of APBI as a standard of care therefore rides on its
ability to match or better WBI in terms of efficacy, quality of life
outcomes, and cost-effectiveness.

Accelerated partial breast irradiation

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