Download Accelerated Partial Breast Irradiation

A variety of techniques for accelerated
partial breast irradiation are available.
Photo courtesy of Lisa Scholder. Hidden Power, 24ʺ × 28ʺ.
Accelerated Partial Breast Irradiation:
A Review and Description of an Early North American
Surgical Experience With the Intrabeam Delivery System
Jeremiah L. Deneve, DO, Richard A. Hoefer, Jr, DO, FACS,
Eleanor E. R. Harris, MD, and Christine Laronga, MD, FACS
Background: Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation
(WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial
demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We
report on our early North American surgical experience using the Intrabeam radiotherapy delivery system
and review the current literature.
Methods: Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive
breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early
postoperative outcome were assessed. A literature review was also performed.
Results: Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and
concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology
with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially
available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety
of APBI techniques currently utilized in clinical practice as well as an istitutional review of our early surgical
experience using the Intrabeam radiotherapy delivery system.
Conclusions: While a variety of APBI techniques are currently available for clinical use, our early North
American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds
moderate operative time and may require creating subcutaneous tissue flaps. The addition of WBI may be
necessary in situations for positive residual margins or microscopic nodal disease in patients who do not
undergo additional surgery.
Introduction
From the Comprehensive Breast Program, Department of Women’s
Oncology (JLD, CL), and the Radiation Oncology Program (EERH)
at the H. Lee Moffitt Cancer Center & Research Institute, Tampa,
Florida, and the Dorothy G. Hoefer Comprehensive Breast Center,
Sentara Cancer Network, Newport News, Virginia (RAH).
Submitted January 3, 2012; accepted May 30, 2012.
Address correspondence to Christine Laronga, MD, FACS, Comprehensive Breast Program, Department of Women’s Oncology, MCCBR PROG, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa,
FL 33612. E-mail: [email protected]
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
October 2012, Vol. 19, No. 4
Breast conservation therapy consisting of breastconserving surgery followed by postoperative whole
breast irradiation is considered the current standard
of practice for patients with early-stage breast cancer.1 Several randomized trials have demonstrated
equivalent overall survival for patients who undergo
breast conservation therapy vs mastectomy.2-4 Whole
breast irradiation is administered in the postoperative
setting as 45 Gy to 50 Gy in daily fractions for 5 consecutive weeks. An additional external beam boost
Cancer Control 295
of 10 Gy to 16 Gy is often delivered to the tumor bed
to further improve local control and decrease local
recurrence rates.5
Rationale for APBI
While overall outcomes are highly favorable for patients who undergo breast conservation therapy with
external beam irradiation, there is growing interest in
alternative irradiation fractionation regimens. These
alternative modalities could provide similar local control while sparing normal breast parenchyma, thereby
improving cosmesis. Additionally, daily round-trips
for up to 6 weeks may be financially and physically
prohibitive for many women. Accelerated partial
breast irradiation (APBI) techniques, delivered as
3D conformal external beam radiotherapy, as intraoperative radiotherapy (IORT), or as interstitial/intracavitary implants have been evaluated in multiple
clinical trials as alternatives to conventional whole
breast irradiation.6-9 Support for the use of APBI
comes from the observation that 80% to 90% of local
recurrences following whole breast irradiation occur
in proximity to the original tumor bed.10-12 APBI offers several theoretical advantages over whole breast
irradiation, including (1) decreased radiation dose to
uninvolved portions of the breast and surrounding
normal organs such as the heart and lungs, and (2)
shortened treatment courses from 5 to 6 weeks to 5
days or less, allowing many women who could not
undergo a conventional postoperative radiotherapy
course due to socioeconomic constraints or comorbidities to choose breast conservation therapy over
mastectomy.10,11,13,14
Patient Selection Criteria for APBI
All patients considered for APBI should be suitable
candidates for breast conservation therapy with earlystage invasive breast cancer and low risk of clinically
occult disease remote from the lumpectomy cavity.
Initial early APBI experiences were complicated by
unacceptably high local recurrence rates, possibly
related to suboptimal patient selection and/or treatment technique.15-19 More recently accepted stringent criteria would have rendered many of these
early patients unsuitable candidates for APBI therapy.
While local recurrence rates have dramatically decreased over the last decade, the lessons observed
from these early pioneering studies highlight several
of the tumor-, treatment-, and patient-related factors
that warrant mentioning when considering potential
eligibility for APBI.
Primary Tumor Characteristics
Primary tumor size (pT) is a significant determinant of
patients who might be considered for APBI therapy.
Early APBI studies included patients with tumor sizes
ranging from 0 cm to 5 cm; the larger sizes (4 cm
to 5 cm) may have contributed to higher local recurrences.16-18,20 The more recent trend has been to treat
296 Cancer Control
smaller primary tumors, ranging in diameter of 0 cm
to 3 cm.21-24 Additionally, larger tumors (> 3 cm) have
been found to have a higher incidence of late softtissue toxicity (ie, fat necrosis) impacting cosmesis,
quality of life, and imaging requirements — another
reason they may be less ideal candidates for APBI.25
Thus patients with primary T3 or T4 tumors should
not undergo breast conservation therapy with APBI.
Multicentricity, defined as the presence of tumor
foci more than 2 cm from the primary lesion, is associated with an increased risk of local recurrence and
is another contraindication to APBI.16,18 The extent
of disease cannot be assessed or adequately treated
using current APBI techniques. Multifocal tumors,
however, defined as separate foci within the same
quadrant, potentially may be treated. While a majority of prospective single-arm APBI trials have not
considered multifocality as an eligibility criterion,
a limited number of centers have included patients
with multifocal (unicentric) tumors.26-28 The American
Society for Radiation Oncology (ASTRO) Task Force
considers patients with multifocality measuring < 2
cm as “suitable” for APBI, whereas those with multifocality measuring < 3 cm as “cautionary” and > 3 cm
as “unsuitable” for APBI.29
Histologic grade has not been routinely included
as a selection criterion in a majority of the prospective APBI studies performed thus far. The centers
that have specifically addressed histologic grade have
limited enrollment to low- or intermediate-grade (I or
II) tumors.10,21-24 The Hungarian randomized trial of
APBI vs whole breast irrdiation demonstrated that histologic grade had no significant impact on long-term
control but that those with high-grade (III) tumors did
have a shorter time to local recurrence (20 months)
than those with low- or intermediate-grade (I-II) tumors (38 months).30,31 Others have demonstrated
tumor grade to be a strong predictor of local recurrence.12 While data remain limited on the long-term
outcome of high-grade tumors treated with APBI, the
ASTRO consensus statement lists “any” tumor grade
as “suitable” criteria for APBI.29
Surgical Margin of Resection
A positive surgical margin is a major determinant
of risk of local recurrence after breast-conserving
therapy.32,33 Five-year local failure rates are better
for those with clear (negative) margins (0%) than for
those with close (4%), focal (6%), or diffusely positive
margins (21%).33 However, data are limited regarding the surgical margin of resection, measured from
the inked surgical margin to the nearest invasive or
associated in situ component, for patients considered
for APBI. Early APBI studies allowed patients with
unknown or focally positive margins, which may have
contributed to higher local recurrences.15,17,18,20,34 Recent studies have used more stringent requirements,
including clear (negative) margins as a selection criterion.24,26,35,36 Limited clinical data are available for
October 2012, Vol. 19, No. 4
patients with negative but close (< 2 mm) surgical
margins. Nonetheless, several centers have begun
to offer APBI to patient with close margins (negative
but tumor within 2 mm to 5 mm) with acceptable
local recurrences and long-term follow-up.8,22,23,27,28,37
Histology
Invasive lobular carcinoma histology has been largely
considered a relative contraindication to APBI due to
its multifocal nature and diffuse pattern of spread. In
the Christie Hospital study, local recurrence rates as
high as 43% were reported for patients with invasive
lobular cancer who received radiotherapy only to the
tumor bed.16 Authors of the German-Austrian multicenter APBI trial, however, reported no significant
difference in 5-year local recurrence rates between
invasive lobular cancer and other histologies.23 The
consensus Task Force recommendation from ASTRO
recommends that patients with invasive lobular histology be considered “cautionary” for undergoing APBI
as clinical data are limited.29 Lobular carcinoma in
situ has largely not been regarded as a separate component of the eligibility criteria in most prospective
single-arm APBI trials.
On the contrary, patients with ductal carcinoma
in situ (DCIS) have largely been excluded from prospective single-arm APBI trials and therefore limited
clinical information is available.7,21,28 Many of these
tumors are multifocal and widespread (extensive disease), both of which are significant predictors of local
recurrence.38 However, some radiation oncologists
treat small (< 3 cm) unifocal DCIS tumors excised
with adequate margins.26 The Task Force recommendation is that small DCIS tumors be included
in the “cautionary” group, whereas those with more
extensive DCIS should be considered “unsuitable”
for APBI.29 Patients whose primary tumors contain
an extensive intraductal component (consisting of
more than 25% of an intraductal carcinoma or DCIS
component) are also generally not recommended to
undergo treatment with APBI, the rationale being
that tumors with extensive intraductal components
behave similarly to pure DCIS tumors. The American
Society of Breast Surgeons (ASBS) MammoSite APBI
trial registry demonstrated a higher association of
ipsilateral breast tumor recurrence (IBTR) in patients
with an extensive intraductal component.39 For this
reason, most authors consider extensive intraductal
component a contraindication to APBI.
Patient Age
Studies have demonstrated that patients aged 60 years
or greater have a lower incidence of IBTR and that
younger patient age is a significant adverse prognostic
factor for local recurrence.5,40-43 For these reasons,
most prospective APBI trials defined eligibility as
women 50 years of age or greater. Many of the early
APBI trials originally had no patient age selection
criteria or included patients > 40 years, which also
October 2012, Vol. 19, No. 4
may have contributed to the early unacceptably high
local recurrence rates observed in those series.16,17,20,44
More recent prospective APBI trials have demonstrated lower local recurrence rates for patients who were
treated at 60 years of age or greater (1.8% to 6.7%)
than those at 40 years or greater (2.6% to 19%).24,28,37,45
Taken together, these studies offer conflicting results
for patients < 50 years of age. Further prospective
studies and additional follow-up are needed to clarify
the role of APBI for this target age population (40 to
60 years of age).46 The ASTRO consensus guideline
considers age 50 to 59 years as a cautionary criterion
and age < 50 as unsuitable. However, the European
Society for Therapeutic Radiology and Oncology (ESTRO) guidelines allow age > 50 as “good candidates”
and age > 40 to 50 as “possible candidates,” with only
age ≤ 40 considered a contraindication.
Other Considerations
The majority of the patients treated with APBI have
had estrogen receptor (ER)-positive tumors and are
thus considered “suitable” based on the ASTRO consensus statement for APBI.29 While several European
and American APBI studies have enrolled hormone
receptor-negative patients, several studies have demonstrated higher local recurrence with ER- or progesterone-negative tumor status. Despite these negative
results for hormone receptor-negative tumors, a lack
of a consensus treating these tumors still exists.47-49
HER2 expression status also remains controversial, as
many studies predate the era of routine HER2 testing, and this parameter is not discussed in either the
ASTRO or ESTRO guidelines. HER2 overexpression
has been associated with higher local recurrence rates
without the use of systemic trastuzumab.50 While further study is required, APBI should perhaps be offered
only to patients with HER2 overexpression if they are
receiving systemic therapy including trastuzumab and
who also meet suitability criteria.
Due to the lack of existing data, the Task Force
recommendation for patients with a personal or family
history of BRCA1 or BRCA2 mutation is that they do
not receive APBI outside of a clinical trial.29 Candidates
for APBI should undergo axillary staging with sentinel
lymph node biopsy or level I/II axillary dissection.
Patients with positive lymph nodes are at a higher risk
of local-regional recurrence and distant failure, and
they are contraindicated for APBI consideration.1,29
A majority of prospective APBI studies have enrolled
only pathologically node-negative patients, which is
the current recommendation for consideration of APBI.
Those patients with isolated tumor cells (< 0.2 mm)
should be considered node-negative.51
The European Society for Therapeutic Radiology
and Oncology (GEC-ESTRO) and ASTRO Task Force
consensus panels have described characteristics for
patients considered to be “low-risk, intermediate-risk,
high-risk” and/or “suitable, cautionary, or unsuitable”
for APBI, respectively. A brief comparison of the
Cancer Control 297
GEC-ESTRO and ASTRO guidelines is described in
Tables 1-3.
APBI is a form of radiotherapy that delivers daily fraction doses of radiation greater than 2 Gy, delivered
in less than or equal to 5 days. Unlike whole breast
irradiation, which treats the entire breast, APBI treats
only the lumpectomy cavity and a surrounding 1 cm to
2 cm margin of breast parenchyma. A variety of APBI
techniques are currently in clinical use today and
differ in their method of radiation delivery, biological effective radiation dose, and clinical application.
Additional experience and follow-up from prospective clinical trials will provide further insight on the
long-term outcome on local control, cosmesis, and
clinical impact of these APBI therapies.
Multicatheter Interstitial Brachytherapy
Multicatheter interstitial brachytherapy was the first
APBI technique described and has had the longest
follow-up with respect to newer modalities.26 It was
initially developed as a boost technique to be delivered
after whole breast irradiation. Multicatheter interstitial
brachytherapy is an invasive technique that requires
precise placement of multiple flexible after-loading
catheters into the tumor bed either free-handed or
using a template guide. The catheters, up to 14 to
20 in number, are placed in parallel planes, approximately 10 mm to 20 mm apart, to ensure adequate
lumpectomy cavity coverage. Computed tomography
guidance and virtual planning have had a significant
impact on catheter placement and treatment planning.52 Irradiation is administered either as low dose
rate (LDR) or high dose rate (HDR) brachytherapy.
Table 1. — Suitable/Low-Risk Candidates for Accelerated Partial Breast
Irradiation Based on ASTRO/ESTRO Guidelines
Table 2. — Cautionary/Intermediate-Risk Candidates for Accelerated
Partial Breast Irradiation Based on ASTRO/ESTRO Guidelines
APBI Techniques
ASTRO29
“Suitable”
Factor
GEC-ESTRO46
“Low Risk”
Patient Factors
ASTRO29
“Cautionary”
Factor
GEC-ESTRO46
“Intermediate Risk”
Patient Factors
Age
≥ 60 yrs
> 50 yrs
Age
50–59 yrs
> 40–50 yrs
BRCA1/2 mutations
Not present
–
BRCA1/2 mutations
–
–
Pathological Factors
Pathological Factors
Tumor size
≤ 2 cm
≤ 30 mm
Tumor size
2.1–3.0 cm
≤ 30 mm
T stage
T1
T1-2
T stage
T0 or T2
T1–2
Margins
Negative
(≥ 2 mm)
Negative
(≥ 2 mm)
Margins
Negative, but close
(< 2 mm)
Negative, but close
(< 2 mm)
Grade
Any
Any
Grade
Any
Any
LVSI
No
Not allowed
LVSI
Limited/focal
Not allowed
Estrogen receptor status
Positive
Any
Estrogen receptor status
Negative
Any
Multicentricity
Unicentric only
Unicentric
Multicentricity
–
Unicentric
Multifocality
Unifocal
(total size < 2 cm)
Unifocal
Multifocality
Unifocal
(total size 2.1–3.0 cm)
Multifocal
(within 2 cm of lesion)
Histology*
Invasive ductal
Invasive ductal
Histology*
Invasive lobular
Invasive ductal
Pure DCIS
Not allowed
Not allowed
Pure DCIS
≤ 3 cm
Allowed
EIC
Not allowed
Not allowed
EIC
≤ 3 cm
Not allowed
Associated LCIS
Allowed
Allowed
Associated LCIS
–
Allowed
pN0 (i–, i+)
pN1mi, pN1a
Not allowed
Not allowed
Nodal Factors
Nodal Factors
N stage**
pN0(i–, i+)
pN0
Treatment Factors
Treatment Factors
Neoadjuvant therapy
Not allowed
Not allowed
* Mucinous, tubular, medullary and colloid allowed.
** Based on sentinel lymph node biopsy or axillary lymph node dissection.
LVSI = lymphovascular space invasion, EIC = extensive intraductal component,
DCIS = ductal carcinoma in situ, LCIS = lobular carcinoma in situ.
298 Cancer Control
N stage**
Neoadjuvant therapy
* ILC, mucinous, tubular, medullary and colloid allowed.
** Based on axillary lymph node dissection.
LVSI = lymphovascular space invasion, EIC = extensive intraductal component,
DCIS = ductal carcinoma in situ, LCIS = lobular carcinoma in situ.
October 2012, Vol. 19, No. 4
LDR requires inpatient admission and delivers 45 Gy
over 3 to 5 days, whereas an HDR implant may be
performed on an outpatient basis, administering 32
Gy to 34 Gy in 8 to 10 fractions (twice daily for 4 to
5 days).26,53
Multicatheter interstitial brachytherapy has several advantages over other APBI techniques. The
flexibility of the multicatheter method allows precise
conformation to the anatomical shape and location of
the irradiated target volume cavity. This method also
has the longest reported experience of any other APBI
technique, and long-term cosmetic results have been
favorable.54,55 Excellent long-term local control rates
(> 5 years) have been reported among several institutions, ranging from 1% to 6%.4,26,35-37,56-58 While these
long-term results are encouraging, the widespread
adoption of interstitial brachytherapy use has been
Table 3. — Unsuitable/High-Risk Candidates for Accelerated Partial
Breast Irradiation Based on ASTRO/GEC-ESTRO Guidelines
ASTRO29
“Cautionary”*
Factor
GEC-ESTRO46
“High Risk”**
Patient Factors
Age
< 50 yrs
< 40 yrs
BRCA1/2 mutations
Present
–
Tumor size
> 3 cm
> 30 mm
T stage
T3–T4
T2, T3, T4
Margins
Positive
Positive
Grade
–
Any
LVSI
Extensive
Not allowed
Estrogen receptor status
Negative
–
Multicentricity
Present
Multicentric
Multifocality
Multifocal
(total size > 3.0 cm)
Multifocal
(≥ 2 cm of lesion)
Histology
–
–
Pure DCIS
> 3 cm
–
EIC
> 3 cm
–
Associated LCIS
–
–
pN1, pN2, pN3
pNx, pN2a
If used
If used
Pathological Factors
Nodal Factors
N stage
Treatment Factors
Neoadjuvant therapy
* If any of these factors are present, the Task Force recommends against APBI
outside of a prospective clinical trial.
** Contraindications for APBI.
LVSI = lymphovascular space invasion, EIC = extensive intraductal component,
DCIS = ductal carcinoma in situ, LCIS = lobular carcinoma in situ.
October 2012, Vol. 19, No. 4
limited to only a few centers because of the expertise
required to perform this technique and the technical
difficulties associated with its application.
MammoSite Balloon Catheter
The MammoSite catheter (Hologic Inc, Marlborough,
MA) is a balloon-based brachytherapy device placed
within the lumpectomy cavity at the time of surgery
(or as a separate procedure after surgery) and was
approved by the US Food and Drug Administration
(FDA) in 2002 as a single interstitial balloon catheter
alternative to multicatheter interstitial brachytherapy.59
The catheter consists of a double lumen catheter with
a balloon at the end and is easier to handle with a
shorter learning curve.60 The balloon is inflated (30-cc
to 70-cc volume) with a mixture of contrast and saline
to conform to the lumpectomy cavity. Brachytherapy
is administered via an HDR source introduced within
the inner lumen of the catheter to the center of the
balloon surface. Irradiation therapy is given in an
outpatient manner, twice a day, over 5 days with a
minimum of 6 hours between treatments. At completion of the last treatment, the balloon is deflated and
the catheter is removed.
Outcome results for APBI using the MammoSite
catheter have generally been favorable; local recurrence rates range between 0% to 5.7% with an intermediate length of follow-up (20 to 60 months).7,22,28,61-63
Vicini et al64 reported on 1,440 patients enrolled in the
ASBS breast brachytherapy registry trial. Thirty-seven
cases (2.6%) of IBTR were observed with a median
follow-up of 60 months, an actuarial 5-year IBTR rate
of 3.8%. Negative hormone receptor status was associated with an increased risk of IBTR for those with
invasive carcinoma, while age (< 50 years) and positive
margin were associated with increased IBTR for DCIS.
Cosmetic results have been reported by several
contemporary clinical studies using the MammoSite
catheter and are improved by proper patient selection
with good or excellent cosmetic outcomes observed
in 84% to 95% of cases.6,61,64,65 Maintaining a balloon
catheter-to-skin distance of at least 7 mm is recommended and is associated with a greater improvement
in cosmesis.22,65 Maintaining the required skin-to-balloon cavity distance may be more difficult in tumors
situated in the upper-inner quadrant or small volume
breast. Short-term toxicity with the MammoSite balloon catheter has been associated with erythema,
edema, and pain.59 Symptomatic seroma is the most
frequently reported long-term toxicity associated with
MammoSite catheter use. Persistent seroma rates
as high as 50% to 72% have been reported in some
smaller series.6,66 The incidence of clinically significant seroma is higher with associated infection and
may be reduced with prophylactic antibiotics.67 The
ASBS MammoSite registry trial of 1,449 cases reported
a 90.6% good or excellent cosmetic outcome, with an
incidence of symptomatic breast seroma formation in
13% and long-term fat necrosis in 2.3%.64
Cancer Control 299
Contura Multiple Lumen Balloon Catheter
The Contura balloon catheter (SenoRx Inc, Aliso Viejo,
CA) differs from the MammoSite catheter in that it
has multiple (four) lumens that allow passage of an
iridium-192 HDR source. The Contura device contains
4 lumens, fixed at 5 mm from a central channel, that
allow passage of the HDR source and conform to
the lumpectomy cavity.68 A vacuum port is present
on the catheter that allows removal of air or fluid
around the lumpectomy cavity, resulting in reproducible radiation dose delivery and increased target
volume coverage.69 The Contura catheter was approved by the FDA in 2007. Early clinical experience
showed that the Contura catheter was well tolerated,
with 100% good/excellent cosmetic outcome and 3%
symptomatic seroma formation observed during short
follow-up of 8 months.70 Three-year follow-up data
have been reported, with a 2% local recurrence rate
and 4.3% symptomatic seroma rate, both similar to
other APBI alternatives of similar follow-up (median
of 36 months).71
Hybrid Brachytherapy Devices
ClearPath Brachytherapy System
ClearPath (North American Scientific Inc, Chatsworth,
CA) is a hybrid device that combines the advantage of
a balloon catheter with multicatheter brachytherapy.
The ClearPath device consists of 6 expandable tubes
around a central catheter that accepts the HDR iridium-192 source. These catheters can be adjusted by
rotating a knob at the base of the device to conform to
the lumpectomy cavity. After ClearPath catheter placement, a rubber sleeve is sutured to the patient and the
base of the catheter is cut off, leaving only the catheters exposed. This avoids cumbersome exposed catheters (a frequent source of patient discomfort and complaint) and allows reduction in the received radiation
skin dose without compromising target volume such
as in situations where inadequate skin distance may
preclude APBI with other techniques (MammoSite).72
Because ClearPath is a relatively new clinical device,
no clinical outcome data currently exist. Dosimetric
comparisons of ClearPath technology with MammoSite
therapy have demonstrated similar target volume coverage with increased normal tissue-sparing.72,73
Strut-Adjusted Volume Implant
The Strut-Adjusted Volume Implant (SAVI) device (Cianna Medical Inc, Aliso Viejo, CA) is a single-entry,
multiple-strutted catheter device that is inserted on
an outpatient basis by a radiation oncologist under
ultrasound guidance. The device consists of a central
strut surrounded by 6 to 10 peripheral struts that can
be expanded to fit a lumpectomy cavity by simple
rotation of a knob at the proximal end of the expansion device.74,75 The expansion of the struts provides
a pressure fit, securing the struts in place with expansion to fill the cavity. Computed tomography
confirmation of catheter placement is required prior
300 Cancer Control
to initiation of radiation therapy. Early experience
with this device involving more than 100 patients
with 21-month follow-up found the SAVI to be well
tolerated, with only 2 symptomatic seromas, 2 patients
with fat necrosis, and 1% recurrence observed.76 In
that series, 5% of the patients would have been ineligible for any balloon brachytherapy and 27% were
ineligible specifically for MammoSite therapy due to
inadequate skin-to-cavity distances.
Noninvasive APBI Techniques
3D Conformational Radiation Therapy
3D conformational external beam radiation therapy
(3D-CRT), a noninvasive alternative to surgical APBI
techniques, uses a linear accelerator-based treatment. Target volume planning is determined based
on computed tomography of the lumpectomy cavity
(confirmed by postoperative changes, seroma cavity,
or surgical clips if placed) with an additional safety
margin of 1 cm to 2 cm. Because the breast is a mobile organ, a larger treatment area may be required
to provide homogenous coverage of the target volume and avoid geographic miss. The homogenous,
uniform target volume coverage applied by 3D-CRT
is thought to result in a more favorable cosmetic outcome with less long-term fibrosis or fat necrosis than
that observed with other APBI techniques. This technique utilizes four to five tangentially oriented noncoplanar beams targeted to the tumor bed. 3D-CRT
delivers 38.5 Gy within 1 week (3.85 Gy twice daily)
based on the radiation dose used for the phase III
National Surgical Adjuvant Breast and Bowel Project
B-39/Radiation Therapy Oncology Group (NSABP/
RTOG) protocol.77
3D-CRT avoids the need for a second invasive surgical procedure and can be performed at most radiation centers. It is easily administered and reproducible, and it does not rely on the operator-dependent
technical demands that other APBI alternatives may
require. One disadvantage to 3D-CRT is that motion
of the breast with normal respiration and daily setup
variation requires a larger target treatment volume.
The clinical target volume is defined as the visible
postoperative tumor bed plus a 1-cm to 1.5-cm margin of surrounding normal tissue. This margin addresses the fact that a majority of local recurrences
occur in the vicinity (within 1 cm to 2 cm) of the
primary lesion.12,78,79 Some have recommended prone
positioning to minimize target tissue movement and
avoid missing the planned target area during treatment.80 Nevertheless, the planned treatment volume
around the lumpectomy cavity is adjusted to account
for breathing motion and differences in setup.81
Chen et al82 reported on the outcome of patients
with stage I or II breast cancer who underwent treatment with 3D-CRT.82 Ninety-four patients were treated
with a median of 4.2 years of follow-up with an ipsilateral in-breast failure observed in 1.1% (1 recurrence), good cosmesis reported in 89%, and long-term
October 2012, Vol. 19, No. 4
fibrosis in 3% of patients. Results from the prospective RTOG-0319 trial treated 52 eligible patients of
58 enrolled and identified similar results.83 With a
median follow-up of 4.5 years, the ipsilateral breast
failure rate was an estimated 6%; two grade 3 toxicities were observed.
A variety of additional noninvasive partial breast
irradiation techniques including intensity-modulated
radiotherapy (IMRT),84 volumetric-modulated arc therapy (VMAT),85 continuous arc rotation of the couch
(C-ARC),86 Accuboost,87,88 and photon beam therapy89
are currently under clinical investigation. Results are
continuing to accrue with these techniques and will
provide additional future information.
Intraoperative Radiotherapy Techniques
Intraoperative radiation therapy (IORT) is an especially attractive APBI treatment option in that it delivers a single dose at the time of initial surgery. Several
centers have begun to investigate the utility of IORT
for patients with low-risk, early-stage invasive cancers
(ie, age > 60 years with T1 N0 ER-positive invasive
ductal carcinoma), either as a boost to the tumor bed
or as sole treatment after partial mastectomy.90-92 Several IORT options are clinically available, including
the Mobetron (IntraOp Medical Corp, Norcross, GA)93
and Novac 7 (Hitesys, Aprilia, Italy)94 devices, which
employ electrons (megavoltage), and the Axxent and
Intrabeam devices, which utilize a kilovoltage source.9
Axxent Electronic Brachytherapy
The Axxent Electronic Brachytherapy System (Xoft
Inc, Fremont, CA) is a novel form of balloon-based
brachytherapy that uses an electronic 50 kilo-voltage radiation source rather than an iridum-192 HDR
source.95 The catheter is a single lumen balloon catheter, similar to the MammoSite catheter, and contains
two additional ports, one for evacuation of air or fluid
and the other for balloon insufflation. The X-ray
source delivers radiation to the patient via a miniature X-ray tube inserted into the central lumen of the
catheter. This approach is unique in that it avoids the
need for an HDR after-loader unit or a shielded radiation room. This increases the potential applicability
of this technology by making it more portable, and
it can be administered intraoperatively as well.95,96
The Axxent electronic brachytherapy catheter was
FDA-approved in 2006.
Axxent brachytherapy, compared to MammoSite,
provides similar target volume coverage with increased
normal tissue sparing.97 Early clinical experience with
Axxent technology has been associated with only
transient short-term toxicity (erythema or blistering)
and no adverse device-related events.98 Because of the
recent introduction of this novel technique, long-term
clinical experience is currently lacking. Early single
and multicenter results, however, have been generally favorable with good cosmesis demonstrated and
without any recurrences observed.96,99
October 2012, Vol. 19, No. 4
Targeted Intraoperative Radiotherapy
The Targeted Intraoperative Radiotherapy (TARGiT)
trial opened in 2000 and randomized more than 2,200
women to post-lumpectomy whole breast irradiation
vs a single IORT dose to the periphery of the tumor
bed.92 Compared with whole breast irradiation, IORT
partial breast irradiation using the Intrabeam System (Carl Zeiss Surgical, Oberkochen, Germany) was
found to be safe and efficacious, with fewer radiotherapy-related complications and without a significant
difference in local recurrence at 4 years of followup (0.95% and 1.2%, respectively). The Intrabeam
system delivers IORT from a source of low energy
X-rays (50 kV maximum) using a spherical solid-state
radio-applicator placed within the tumor bed following surgical extirpation. Phase II studies have also
demonstrated safety and tolerability when targeted
IORT is delivered as a boost alternative followed by
standard whole breast external beam irradiation.45,100
The Intrabeam device was recently approved for
clinical use in North America in low-risk, early-stage
breast cancer patients, and a number of centers have
adopted this technology. Use of the device at the
Dorothy G. Hoefer Comprehensive Breast Center
began in 2009 and at Moffitt Cancer Center in January 2011 as among the first North American centers
to employ this method of APBI. We herein report on
our early surgical experience at Moffitt Cancer Center
using the Intrabeam device as definitive therapy for
a predefined low-risk patient population with earlystage invasive breast cancer.
Methods
A single-institution study approved by the institutional
review board was performed on a prospectively maintained database of patients who underwent targeted
intraoperative radiotherapy at the time of initial surgery for early-stage breast cancer. A multidisciplinary
APBI pathway was developed based on ASTRO guidelines and was approved by a consensus panel of clinicians within the Department of Women’s Oncology
at Moffitt Cancer Center consisting of breast-specific
surgical oncologists, medical oncologists, radiation
oncologists, radiologists, and pathologists.
Eligibility criteria included postmenopausal women
greater than 60 years of age who were postmenopausal
with ER-positive, invasive ductal histology. All patients
included were breast conservation candidates with primary clinical tumors size < 3.1 cm, were clinically node
negative, and had received no prior neoadjuvant treatment. Invasive tumors with limited lymphovascular
invasion and/or HER2-positive disease on core needle
biopsy were considered acceptable. Patients underwent
informed consent discussion regarding the risk benefits
and alternatives to IORT with the Intrabeam delivery
system. IORT was planned for delivery at the time of
initial surgery (partial mastectomy) using a predetermined applicator based on dimensions of the primary
tumor and the breast excision specimen cavity. The
Cancer Control 301
duration of IORT in minutes (generally 15 to 25 minutes) was determined based on the chosen size of the
radio-applicator to deliver 20 Gy of targeted radiation to
the lumpectomy cavity. Intraoperative ultrasound was
used to measure and confirm a ≥ 1-cm skin-to-surface
of applicator distance in superior, inferior, medial, and
lateral dimensions relative to the radio-applicator. Subcutaneous tissue flaps were created when necessary
to obtain at least a 1-cm margin if needed. Skin was
retracted at least 1 cm from the applicator surface-shaft
interface using the Lone Star Retractor System (CooperSurgical Inc, Stafford, TX).
The sequence of surgery was to first perform a
sentinel node biopsy, if appropriate. While awaiting
the touch preparation (hereafter “touch prep”) analysis
of the sentinel lymph node(s), the (needle-localized)
partial mastectomy was performed. An intraoperative
specimen radiograph was obtained and gross evaluation of the specimen was conducted for margin assessment. Any margin grossly less than 5 mm was
reexcised intraoperatively at this initial surgery. IORT
was then delivered as “intended” definitive therapy at
the time of initial surgery if the sentinel lymph node
was negative on touch prep analysis and the gross
margins from tumor to inked surface were greater than
5 mm. Alternatively, if the patient had an excisional
biopsy diagnosing her cancer, IORT was performed at
the time of reexcision of margins for close (< 2 mm)
microscopic margins. When final pathology confirmed
histologically that all margins were negative, as well as
the sentinel nodes if applicable, then no further radiation was given. Additionally, if on final pathology, postpartial mastectomy with IORT, there was one focally
close margin (< 2 mm), reexcision was not performed.
However, if the final pathology margin was positive or
more than focally close to the margin, reexcision was
required. If these subsequent reexcision margins were
cancer-free, no further radiation treatment was recommended. However, if any reexcision margin specimens
contained cancer, despite negative final margins, those
patients were treated with whole breast irradiation with
the IORT replacing the external beam boost. Similarly,
if the sentinel lymph node was positive at the time of
initial surgery, IORT was delivered as a boost (and not
as definitive therapy), and whole breast irradiation was
subsequently recommended.
For patients who required adjuvant chemotherapy
and/or whole breast irradiation after initial resection
and delivery of IORT, chemotherapy was delivered
prior to administration of whole breast irradiation.
Patients with final pathology specimens demonstrating
extensive lymphovascular invasion or other adverse
prognostic factors (extensive intraductal component,
invasive lobular histology, HER2-positive) were offered
whole breast irradiation on a case-by-case basis. All
patients underwent unilateral digital mammography
and focused breast ultrasound of the lumpectomy site
at about the 6-month follow-up visit. The development of new calcifications or the presence of a seroma
302 Cancer Control
was noted by the interpreting radiologist. Postoperative physical examination findings around the IORT
site included skin contour, hyperemia, erythema, and
palpable seroma. Descriptive statistics were recorded
using SPSS software.
Results
Forty-two patients underwent targeted IORT with
the Intrabeam delivery system at the time of breastconserving surgery. The median patient age was 71
years (range, 54 to 88 years). All patients treated were
postmenopausal, 41 patients (98%) were ER-positive,
and 39 patients (93%) were progesterone receptorpositive. Tumor location involved the upper outer
quadrant in 28 patients (67%), upper inner quadrant
in 4 (10%), central region in 6 (14%), lower outer
quadrant in 3 patients (7%,) and lower inner quadrant
in 1 patient (2%). Final pathology was invasive ductal carcinoma in 38 patients (91%), invasive lobular
carcinoma in 2 patients (5%), DCIS in 1 patient (2%),
and invasive mammary carcinoma in 1 patient (2%).
Twenty-seven patients (64%) had associated DCIS
within the excised specimen. Median invasive tumor
size was 1.0 cm (range, 0.2 cm to 3.5 cm), with 18
patients (43%) having low-grade tumors, 23 patients
(55%) with intermediate-grade tumors, and 1 patient
(2%) with high-grade tumors. Sentinel lymph node
status was available in 40 patients. One patient (2%)
refused sentinel lymph node biopsy and the second
patient underwent attempted axillary exploration after previously having ipsilateral breast conservation
surgery with axillary dissection 10 years prior. Nodal
status was microscopically negative (N0i–) in 36 patients (86%), and 4 (10%) had microscopically positive (N1) nodal involvement on final pathology. No
patient underwent completion axillary lymph node
dissection (Table 4).
All patients received a single dose of preoperative
intravenous antibiotics and then underwent breastconserving surgery with sentinel lymph node biopsy
followed by IORT using the Intrabeam device. An
IORT dose of 20 Gy was delivered to all patients for
a median IORT duration of 25 minutes (range, 15 to
30 minutes). IORT was administered using a 3-cm
radio-applicator in 34 patients (81%) or a 3.5-cm radioapplicator in 8 patients (19%). Subcutaneous tissue
flaps were created in 21 patients (50%) to accommodate the radio-applicator within the tumor bed and
maintain the appropriate skin-to-surface of applicator distance of > 1 cm. Median operative time for
(needle localized) partial mastectomy, sentinel lymph
node biopsy, and delivery of IORT was 119 minutes
(range, 90 to 153 minutes). No patient received postoperative antibiotics upon discharge home from the
recovery room.
Initial intraoperative gross/touch prep of margins
was negative in 31 patients (74%), close (< 2 mm) in
7 patients (17%), and positive in 4 patients (10%).
Twenty-eight patients (67%) underwent synchronous
October 2012, Vol. 19, No. 4
intraoperative excision of additional margins based
on touch prep analysis or gross evaluation. Ten patients (24%) underwent subsequent reexcision for
close (< 2 mm) or positive microscopic margins after
lumpectomy. Final pathological margin was negative
in 39 patients (93%) and focally close (< 2 mm) in
the remaining 3 patients (7%). No patient underwent
mastectomy in the treatment cohort (Table 5).
Adjuvant whole breast irradiation was given to
8 patients (19%) due to the following factors: (1) 1
patient with a close final margin and a positive sentinel lymph node biopsy, (2) 2 patients with negative
margins but a positive sentinel lymph node biopsy on
serial hematoxylin-eosin (H&E) staining who opted out
of a complete axillary node dissection, (3) 3 patients
with close margins, (4) 1 patient with invasive lobular
histology on final pathology, and (5) 1 patient who
Table 4. — Demographics and Histopathology for 42 Patients
Undergoing Intraoperative Radiotherapy With Intrabeam
Variable
Age, median in yrs (range)
N
71 (54–88)
Primary tumor location (quadrant)
Central
had and ipsilateral new primary who had previously
undergone lumpectomy/axillary dissection/whole
breast irradiation. The Oncotype DX assay (Genomic
Health Inc, Redwood City, CA) to determine risk of
recurrence was performed in 18 patients (43%) with a
median recurrence score of 21 (range, 4 to 46). Two
patients had their tumor specimen sent for Oncotype
DX analysis but had insufficient tissue for RNA analysis
to allow risk of recurrence determination. Five patients
(12%) received adjuvant chemotherapy in addition to
a planned aromatase inhibitor, while an aromatase
inhibitor therapy alone was given to 34 patients (81%).
At a median of 15 days to first postoperative examination (range, 8 to 50 days), 15 patients (36%)
had evidence of IORT-related hyperemia/erythema
on physical examination without requiring antibiotics,
14 (33%) had a palpable seroma, and 2 patients (5%)
developed cellulitis, 1 requiring surgical drainage 9
days postoperatively. Five patients (12%) experienced
Table 5 — Delivery of Intraoperative Radiation Therapy (IORT)
for 42 Patients Treated at Moffitt Cancer Center at the
Time of Breast-Conserving Surgery
Variable
6 (14%)
N
Lumpectomy/Partial Mastectomy
42 (100%)
Sentinel Lymph Node Biopsy
40 (95%)
Upper outer
28 (67%)
Upper inner
4 (10%)
Reexcision
10 (24%)
Lower outer
3 (7%)
Tissue flaps
21 (50%)
Lower inner
1 (2%)
IORT applicator diameter
Histology
3 cm
34 (81%)
3.5 cm
8 (19%)
Ductal carcinoma in situ
1 (2%)
Invasive ductal carcinoma
38 (91%)
Invasive lobular carcinoma
2 (5%)
Length of IORT duration, median in minutes (range)
1 (2%)
IORT applicator margins, median in cm (range)
Invasive mammary carcinoma
Associated ductal carcinoma in situ
Tumor size, median in cm (range)
IORT dose (Gy at surface)
20
25 (15–30)
27 (64%)
Medial
1.0 (0.2–3.5)
Lateral
1.80 (1–3.0)
Superior
1.70 (1–2.8)
Inferior
1.84 (1–3.3)
Tumor classification
1.80 (1–3.4)
Tis
1 (2%)
T1a
3 (7%)
T1b
23 (55%)
Negative touch prep (N = 40)
39 (93%)
T1c
13 (31%)
Additional intraoperative margin
28 (67%)
T2
2 (5%)
Tumor grade
Operative time, median in minutes (range)
119 (90–153)
Margin status
Initial
Low
18 (43%)
Negative
Intermediate
23 (55%)
Close (< 2 mm)
7 (17%)
Positive
4 (10%)
High
1 (2%)
Nodal status (N = 40)
N0i–
N1
October 2012, Vol. 19, No. 4
31 (74%)
Final
36 (86%)
4 (10%)
Negative
Close (< 2 mm)
39 (93%)
3 (7%)
Cancer Control 303
postoperative complications: abscess requiring drainage (1), cellulitis (2), infected seroma requiring aspiration (1), and hematoma (1). Fourteen patients (50%)
reached the 6-month follow-up mark (up to December
2011). Eleven patients underwent planned 6-month
breast ultrasound, 9 of whom had sonographic evidence of seroma formation with a median seroma size
of 3.4 cm (range, 1 cm to 4 cm). Six-month physical
examination findings included noninfectious localized
Table 6. — Postoperative Examination Findings and Adjuvant Treatment
Variable
Oncotype testing*
N
18 (43%)
Recurrence score (range)
21 (4–46)
10-yr recurrence (%)
12 (4–31)
Oncotype DX classification*
8 (44%)
Low
5 (28%)
Intermediate
1 (6%)
High
2 (11%)
Unknown
8 (19%)
Whole breast irradiation
Close margins (< 2 mm)
3
Close margin/(+) sentinel lymph node biopsy
1
Positive sentinel lymph node biopsy
2
Invasive lobular carcinoma
1
Prior ipsilateral whole breast irradiation/ALND
1
Chemotherapy
Aromatase inhibitor
Complication
5 (12%)
34 (81%)
5 (12%)
Cellulitis/abscess
2
Hematoma
1
Seroma requiring aspiration
1
Postoperative examination findings
IORT-associated hyperemia
15 (36%)
Seroma
14 (33%)
Cellulitis
2 (5%)
6-mo postoperative examination findings (N = 14)**
Hyperemia
4 (10%)
Clinical seroma
5 (12%)
Ultrasound seroma
9 (21%)
Ultrasound seroma size, median in cm (range)
3.4 (1–4)
Scar retraction
1 (2%)
Cellulitis
1 (2%)
* Oncotype DX assay performed in 18 patients; only 16 had sufficient material
for analysis.
** 6-month follow-up as of December 2011.
304 Cancer Control
hyperemia (4), asymptomatic palpable seroma (5),
scar retraction (1), and cellulitis (1). With a median
follow-up of 3 months (range, 1 to 13 months), there
were no local recurrences (Table 6).
Discussion
Initial experience using the Intrabeam delivery system
originates from its application in treating metastatic
brain metastases.101,102 This led others to explore
additional application alternatives for other disease
process. The rationale for delivery of partial breast
irradiation with IORT or other techniques in breast
cancer is based on the observation that a majority of
local recurrences after breast conservation therapy occur within the vicinity of the primary tumor.103 Initial
phase II studies demonstrated IORT use in patients
with low-risk breast cancers to be safe and feasible.100
Furthermore, when given as a boost, IORT was associated with a low recurrence rate when compared to a
conventional 5- to 6-week regimen with whole breast
irradiation.45 Results were recently reported from a
prospective randomized phase III trial (TARGiT-A)
conducted primarily in Europe and selected centers
in North America, comparing targeted IORT with Intrabeam to whole breast irradiation.92 This international multicenter, noninferiority trial demonstrated
that IORT delivery with Intrabeam resulted in similarly
low local recurrence rates compared to several weeks
of whole breast irradiation for selected patients. One
of the sentinel centers in North America using IORT
(Dorothy G. Hoefer Breast Comprehensive Center)
enrolled several patients in the TARGiT-A trial and
observed no significant difference in skin-related toxicity or pain requirements when compared to those
not receiving IORT (separate internal review, R.H).
In the TARGiT-A trial, patients were selected as
candidates for IORT if they had early-stage invasive
breast cancers (generally T1 or T2 primary tumors, <
3.5 cm).92 Fifty percent had tumors between 1 cm to
2 cm in size, with 14% having tumors > 2 cm. Our
patient population tended to be older (median age
72.5 years) than those treated in the TARGiT-A trial
and with a smaller tumor size. The median tumor
size treated with IORT was 0.95 cm, with the largest
tumor treated measuring 2 cm. Ninety-three percent
of patients had invasive ductal histology while 1 patient had DCIS.
The technique describing the intraoperative delivery of IORT using the Intrabeam device has been
previously described.104 At Moffitt Cancer Center, the
administration of IORT with Intrabeam was found to
be relatively simple to implement technically, with
minimal addition to overall length of the operation.
Initial reports noted that IORT administration added
generally about 45 minutes of additional length to the
operation. This compares favorably as far as overall
time and cost savings when considering that a typical
6-week postoperative radiotherapy course involves 6
to 7 hours of radiotherapy room time with 30 to 60
October 2012, Vol. 19, No. 4
hours of patient time.103,104 Moffitt Cancer Center’s
total median operative time was 123 minutes. Considering that the length of IORT generally lasted 20 to
25 minutes, allowing also a few minutes for machine
preparation, ultrasound assessment of skin to surface
of applicator distance, potential creation of subcutaneous tissue flaps, placement of the radio-applicator,
and removal at the completion of IORT, the entire
delivery process did not significantly lengthen the
entire duration of the operation. Furthermore, for
the majority of patients who do not require additional
radiotherapy or margin reexcision, the option of completing radiotherapy at the time of surgical excision
is an attractive treatment alternative.
IORT with Intrabeam delivers 20 Gy of radiotherapy at the surface of the applicator, with 5 Gy
to 6 Gy delivered at a distance of 1 cm from the applicator.100 The relative biologic effectiveness (RBE)
of low-energy photons modeled using the linearquadratic formula as a function of depth from the
applicator surface demonstrates a higher RBE closer
to the applicator surface compared to conventional
fractionation, with a lower RBE at greater distances.105
These models translate to a higher local control rate
nearer to the applicator that partly compensates for
reduced local control at greater distances and suggest
that overall local control rates should be equivalent
to conventionally fractionated radiotherapy up to 10
mm from the applicator surface.
At Moffitt Cancer Center, other technical adjuncts
were found to be useful during the administration of
IORT to avoid skin-related toxicity. Maintaining a distance of at least 1 cm between the applicator and the
nearest skin margin is important as multiple authors
have reported skin-related complications when this
distance is not maintained.92,100 Wenz et al106 observed
the development of grade III fibrosis with hyperpigmentation and skin retraction in 1 patient treated when
skin distance was kept < 5 mm from the applicator
during treatment. Moffitt Cancer Center utilized intraoperative ultrasound to ensure that a safe distance
was maintained prior to the delivery of IORT (Table
5). Lone Star tissue hooks (CooperSurgical Inc, Stafford, TX) placed circumferentially around the wound
helped to maintain this distance. We also wrapped the
neck of the applicator with a saline-soaked radiolucent sponge to decrease the dead space and minimize
movement of the skin around the applicator during
treatment. In some patients (68%), we created subcutaneous tissue flaps (within the breast parenchyma,
not the skin dermis) to accommodate better applicator
placement, maximizing tissue apposition and breast
cavity area coverage with the applicator. In certain
situations (superficially oriented tumors), an ellipse
of skin may need to be excised to accommodate the
applicator device and avoid unintended skin overexposure. A tungsten-impregnated polyurethane sheet
was utilized on the surface of all patients to protect
the skin and surrounding tissues from radiation scatOctober 2012, Vol. 19, No. 4
ter. To save time, IORT was delivered after the partial
mastectomy/sentinel lymph node biopsy had been
performed. We did not initiate IORT until we were
satisfied that margins were clear, reexcising a close
or positive margin if necessary, before delivering the
radiation dose. This allowed minimal interruption in
the cadence of the procedure while awaiting touch
prep analysis of the sentinel lymph node.
Initial postoperative physical examination findings
were mild, and the combined surgery with IORT was
generally well tolerated in the Moffitt Cancer Center
experience. Forty-six percent of patients had evidence
of localized hyperemia at initial postoperative visit. At
6-month follow-up (N = 14 as of December 2011), this
was markedly reduced as only 14% had residual evidence of noninfectious hyperemia. Ten patients (36%)
had evidence of an asymptomatic palpable seroma at
first postoperative visit. At Moffitt Cancer Center, we
performed a routine 6-month follow-up breast ultrasound to measure for residual seroma. Nine patients
(32%) had ultrasound evidence of residual seroma
present. On physical examination, however, only 5
patients (18%) had a palpable seroma appreciable at
6-month follow-up, all of which were asymptomatic.
This finding was one of the major IORT-related toxicities observed within the TARGiT-A trial. Patients in
the IORT arm were more likely to develop clinically
significant seroma that required 3 or more aspirations.92 Only 1 patient required seroma aspiration. In
that situation, the seroma became secondarily infected,
was aspirated, and ultimately resolved after a short
course of oral antibiotics. One patient developed an
early postoperative methicillin-resistant Staphylococcus aureus (MRSA) abscess requiring operative drainage at postoperative day 9. Another patient who required whole breast irradiation after IORT developed
delayed-onset cellulitis approximately 4 months after
her procedure. She did not have evidence of cellulitis at her first two postoperative visits. The toxicity
ultimately resolved with oral antibiotic therapy alone.
The timing of external beam radiation therapy after
IORT is critical as those who receive additional whole
breast irradiation within 36 days of IORT are more
likely to develop late toxicity findings characterized
by fibrosis, retraction, or breast pain.106 While Moffitt
Cancer Center did not specifically address “pain” as
an endpoint, others have reported that IORT is not
associated with increased risk of the development of
persistent pain after breast cancer treatment when
compared to external beam radiation therapy.107
Pain was recorded at the Dorothy G. Hoefer Comprehensive Breast Center where 24 women having
Intrabeam as the “boost” followed by standard whole
breast irradiation were compared to 24 women having the “boost” and the whole breast radiation all as
external beam following definitive surgery (personal
communication, R. H., December 15, 2011). Postoperative pain as reported by narcotic prescription use
was not significantly different between the two groups
Cancer Control 305
(mean 1.1 vs 0.5; P = .2). Other findings were similar
to the main TARGiT-A trial and Moffitt Cancer Center’s results. The median age in the Intrabeam group
was 63 years (range, 44 to 80 years), and the median
follow-up was 4 months. Six women had grade 1 skin
erythema. No higher skin reactions were evident at
1 month following surgery. Two patients developed
delayed infections of their seroma cavities 1 month
following completion of the external beam regimen.
The median seroma size of IORT-treated patients at 1
month was 24.0 cc (range, 4.9 cc to 190.0 cc), while
the median seroma size for non-IORT patients was
2.4 cc (range, 0 cc to 14.3 cc; P < .01).
Unlike our counterparts in Virginia at the Dorothy G. Hoefer Comprehensive Breast Center, whole
breast irradiation was given after targeted IORT to a
total of only 4 patients (14%) at Moffitt Cancer Center.
Three patients (11%) had whole breast irradiation
for a positive sentinel lymph node biopsy on final
pathology (one touch prep negative, the other with a
single cluster on touch prep analysis, one touch prep
positive). After counseling of the risks and benefits,
all 3 patients opted not to undergo completion axillary lymph node dissection. Whole breast irradiation
treatment fields were adjusted to include level I/II axillary lymph node regions. The remaining patient was
treated with whole breast irradiation after IORT for
a positive final pathological margin after reexcision.
Interestingly, in phase II reports of IORT given as a
“boost” combined with external whole breast radiation therapy, patients with focal microscopic margins
who did not undergo reexcision did not experience
an increased local recurrence rate, possibly due to
more accurate targeting and timeliness of treatment.45
Although not a primary endpoint of this study due to
limited follow-up, no recurrences were observed in
this short treatment experience.
Conclusions
A variety of accelerated partial breast irradiation
(APBI) techniques are available. The most appropriate treatment should be selected on an individual
basis according to patient and clinician preference,
institutional capabilities, and familiarity with the risk
and benefits of the most common APBI techniques. At
Moffitt Cancer Center, while a variety of APBI methods
are currently utilized, intraoperative radiation therapy
(IORT) was found to be a suitable treatment alternative for highly selected patients with early-stage invasive breast cancers who meet the suitability criteria for
accelerated partial breast irradiation. The technique
is easily applied with only minimal increase in operative length. IORT can be intended for use as a boost
followed by whole breast irradiation in situations of
unfavorable histopathology. IORT-related toxicity is
acceptable and avoids the time inconvenience of a
5- to 6-week postoperative course of whole breast irradiation, making it an attractive treatment alternative
for a significant group of patients.
306 Cancer Control
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