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Breast Cancer: New Radiation Treatment Options

Breast Cancer: New Radiation Treatment Options

ABSTRACT: Conventional radiotherapeutic treatment for early and advanced breast cancer has been based on broad-field radiation treatment principles that date back several decades. Although these strategies have been successful, newer techniques now offer the ability to incorporate improved target imaging, dosimetric planning, and treatment delivery into the treatment design. These newer techniques include accelerated partial-breast irradiation and hypofractionated whole-breast irradiation for early-stage breast cancer, and intensity-modulated radiotherapy (IMRT) for both early and advanced breast cancer. Accelerated partial- breast irradiation and hypofractionated whole-breast radiotherapy are treatment approaches that promise both reduced overall treatment times and the potential for increased use of breast-conservation therapy. IMRT offers unparalleled dose homogeneity and conformality that enables dose reduction to normal structures with the potential to reduce treatment toxicity and improve cosmesis. Based on the published literature, an increasing number of treatment facilities are offering treatment with these techniques. However, further clinical study remains important to thoroughly define the appropriate clinical setting, patient selection criteria, and limitations for each of these innovative treatment approaches.

Radiotherapy has long since established
itself as integral in
the treatment of breast cancer.
From early-stage to locally advanced
disease, radiotherapy has been incorporated
into the treatment plan for
patients with breast cancer, based upon
the known reduction in the risk of
locoregional failure and evidence suggesting
an improvement in overall survival.[
1-4] The extent of the areas
targeted for treatment has been historically
based on previously established
surgical principles, pathologic findings,
and failure patterns. This has resulted
in broad-field irradiation, encompassing
the whole breast and/or chest wall
with or without regional nodes.

These original broad fields were
simplistic in design and limited by
the planning and treatment delivery
systems available. However, because
of their simplicity, success in reducing
disease recurrence, and ease of
implementation, these treatment techniques
quickly became widely adopted.
In fact, the majority of treatment
centers continue to use these same
general disease management principles
and treatment approaches originally
designed and practiced in the
1970s and 1980s. Although upgraded
field-matching techniques and com
puted tomography (CT)-based treatment
planning have been incorporated,
only minimal modifications
have been made until recently.

Whole-breast radiotherapy has
routinely provided acceptable local
control rates and cosmetic outcomes.[
1,2,5] However, despite the
excellent results, a surprising number
of women-more than half-alternatively
undergo a mastectomy or breastconserving
surgery without the
recommended adjuvant radiotherapy.[
6,7] Although patient preference
may account for some of these choices,
many appear to take this course
due to the time and travel difficulties
presented by the standard 6 weeks of
daily radiotherapy. Others balk at the
recommended radiotherapy out of fear
of toxicity.

Improving Radiation
Treatment Designs

Recent investigations into the radiation
treatment of breast cancer allow
the incorporation of improved
target imaging, dosimetric planning,
and treatment delivery into the treatment
design. With early positive evidence,
this treatment technology is
now beginning to disseminate and
become more commonly practiced in
the United States. New treatment techniques
that utilize this technology offer
the reduction of overall treatment
time, optimized homogeneity of dose
delivery, and improved dose conformality
to the target. New radiation
treatment approaches include accelerated
partial-breast irradiation and
hypofractionated whole-breast irradiation
for early-stage breast cancer, and
intensity-modulated radiotherapy
(IMRT) for both early and advanced
breast cancer.

Determining the Treatment Target
The combination of radiographic
imaging and radiation treatment planning
continue to advance the specialty
of radiation oncology, providing
the ability to create highly conformal
dosimetric plans. To maximize the
effectiveness of this process, the treatment
target must be well imaged and
clearly defined. In breast-conservation
therapy, the convention is to treat
the whole breast. However, whether
measured by physical exam or CT
evaluation, the extent of breast tissue
is difficult to delineate.[8] With con-
continued study, it has become obvious
that the whole-breast target volume is
frequently not completely encompassed
within the bounds of standard
tangential fields. Despite this, local
control rates approach 95% in contemporary
studies.

On the other hand, knowing that
not all patients with early-stage breast
cancer benefit from postlumpectomy
radiotherapy (approximately 60%),
many studies have searched for a reliably
identifiable subgroup of breast
cancer patients who might be safely
excused from postlumpectomy radiation.[
9,10] This subgroup has not yet
been identified, and therefore, it is
recommended that all patients should
complete radiation therapy following
breast-conserving therapy. This logic
leads us to the conclusion that the size
of the target requiring treatment following
lumpectomy is greater than
the lumpectomy cavity itself but less
than the whole breast.

Development of
Partial-Breast Irradiation

In the early 1990s, the problem of
physician and patient compliance with
recommended postlumpectomy radiotherapy
was confronted with a proposal
suggesting that if the target to
be treated following lumpectomy is
not the whole breast, but rather, a
reduced volume of breast tissue delineated
by a margin of tissue around
the lumpectomy cavity, then the treatment
time could possibly be reduced
to 5 days, ie, accelerated partial-breast
irradiation. Clinical data have documented
that the overwhelming majority
of in-breast failures following
breast-conservation therapy are in the
immediate vicinity of the lumpectomy
cavity (referred to as true recurrences).
Although the frequency of
these true recurrences is greatly reduced
with postlumpectomy radiotherapy,
the location of the majority
of in-breast failures remains at the
site of lumpectomy.[2,11,12]

Interestingly, the pattern of "elsewhere
failures" (in-breast failures remote
from the site of lumpectomy)
remains infrequent (< 5%) and unaltered
with the addition of externalbeam
radiotherapy. These data support
the concept that the impact of whole
wholebreast
radiotherapy is exclusively at
the site of the original primary lesion
and that it does not have the ability to
prevent new primary disease from
arising elsewhere in the breast at a
later date.[13] The clinical failure pattern
data suggest that accelerated
partial-breast irradiation should be
successful and equivalent to standard
whole-breast radiotherapy. However,
delineation of the target requiring
treatment is not yet clearly defined.

Shortcomings of
Pathologic Studies

There has been considerable speculation
on how far microscopic disease
might extend from the cavity
edge. The most logical place to look
for guidance in defining the target
would be the pathologic literature, but
little contemporary guidance is available.
The classic pathologic studies
examining mastectomy specimens are
now over 20 years old. It would be
inappropriate to extrapolate the findings
from these studies to patients
treated in the modern era, where advanced
mammographic technology
allows earlier detection, and modern
surgical and pathologic techniques
enable the removal of malignant lesions
with microscopically negative
margins. Unfortunately, there is a paucity
of contemporary pathologic studies
that address this question.

To date, three published studies
have focused on the distance of microscopic
disease extension from the
primary lesion.[14-16] These studies
suggest that the microscopic extension
of disease beyond the primary
lesion is no greater than 1 cm in a
population of patients more than 45
to 50 years old. The maximal disease
extension in younger patients was documented
to be beyond 1 cm. Limitations
of these studies include low
patient numbers, measurement of the
extension of ductal carcinoma in situ
only, and difficulty in extrapolating
the measured distance from the edge
of the primary lesion to a case where
the surgeon obtained a negative microscopic
margin.

Although these pathologic studies
can be criticized as to their relevance,
they support the concept of limitedfield
radiotherapy following lumpec-
tomy for early-stage breast cancer.
Relevant pathologic studies refuting
the concept of accelerated partialbreast
irradiation and supporting the
need for whole-breast radiotherapy
have not been identified.

Accelerated Partial-Breast
Irradiation

For accelerated partial-breast irradiation
to be accepted into the common
practice of radiation oncology,
treatment techniques that are safe and
reproducible need to be available, and
data demonstrating equivalence to
standard breast-conservation therapy
must be reported. Presently, reports
in the literature begin to support both
of these requirements. Brachytherapy,
three-dimensional (3D) externalbeam,
and intraoperative radiotherapy
have been the three accelerated partial-
breast irradiation treatment approaches
investigated.

Brachytherapy
In the United States, a fractionated
course of high-dose-rate brachytherapy
has been the primary focus
of treatment delivery. Multicatheter
brachytherapy was the initial treatment
technique used at the onset of
accelerated partial-breast irradiation
and is the technique used in the experiences
reported with the longest
follow-up. Guidelines for implant construction
were based on the experience
generated from the era prior to
the widespread use of electrons, when
multicatheter brachytherapy was used
to deliver a boost dose to the surgical
bed in addition to whole-breast radiotherapy.

Building on this experience, coupled
with the brachytherapy-only
guidelines for sarcoma treatment from
Memorial Sloan-Kettering, a dose of
45 Gy low-dose-rate brachytherapy
was delivered to the surgical bed plus
a 1-to 2-cm margin.[17] Over time,
this was converted to high-dose-rate
brachytherapy for added control over
planning and dose delivery, and for
the benefit of outpatient treatment and
increased safety for the faculty and
staff.

Although criticized for its operator
dependency and associated learn-
learning
curve when first starting, the incorporation
of radiologic imaging in
the guidance of catheter placement in
concert with 3D treatment planning
has greatly reduced these challenges.[
18,19] Regardless, there will always
be some degree of a learning
curve when starting, and there is no
possible way to remove the distressing
appearance of the breast when
multiple catheters are in place.

  • MammoSite-The MammoSite
    Radiation Therapy System was developed
    to address the difficulties involved
    in multicatheter brachytherapy
    with the goal of simplifying the procedure,
    improving the reproducibility
    of dose delivery, and therefore, increasing
    the availability of accelerated
    partial-breast irradiation. The
    research and development of this
    device has focused on the ability to
    reproduce the target coverage and dosimetry
    achieved with published multicatheter
    brachytherapy techniques.

    The MammoSite Radiation Therapy
    System is composed of a 15-cm
    catheter that is 6 mm in diameter
    (Figure 1). At the distal end of the
    catheter is a balloon that can be symmetrically
    inflated to a sphere with a
    4- to 5-cm diameter, or a larger size is
    available that inflates to 5 to 6 cm.
    The balloon is placed and inflated in
    the lumpectomy cavity with the catheter
    exiting either through the lumpectomy
    incision or a separate exit
    wound. Placement is easily accomplished
    at the time of lumpectomy or
    postlumpectomy and placed by the
    involved surgeon or radiation oncologist.
    When properly placed, treatment
    is delivered to a uniform 1-cm
    depth from the balloon surface.[20,21]

    Since the time of US Food and
    Drug Administration approval in
    May 2002, use of the system has been
    adopted in many locations across the
    country. It is estimated that more than
    4,000 balloons have been used for
    treatment since that time.

3D Conformal External-Beam
Radiotherapy

The latest partial-breast technique
to be investigated is 3D conformal
external-beam radiotherapy. The
ability to deliver a similarly conformal
dose to the target with a noninvasive
approach is attractive to both
patients and physicians. Pilot studies
have been completed, and a national
phase I/II trial has recently been completed.[
22,23] Unique to this treatment
approach is the challenge of
adjusting for patient setup error and
breathing motion, and assuring that
the homogeneous dose delivered is
radiobiologically equivalent to the relatively
inhomogeneous dose delivered
with brachytherapy.

The William Beaumont Hospital
recently published an update of their
pilot experience with 3D conformal
partial-breast irradiation. A total of
31 patients have been treated with a
median follow-up of 10 months, and
15 patients have been followed for at
least 1 year. The described approach
includes strict normal tissue dose restrictions,
defining the clinical target
volume (CTV) as the lumpectomy
cavity plus 1 to 1.5 cm, and the planning
target volume (PTV) as the 1-cm
expansion of the CTV. This additional
PTV margin was applied to address
the potential for setup error and breathing
motion.

A treatment scheme of 34 Gy in 10
fractions was initially used for six patients
and then altered to 38.5 Gy in
10 fractions. The reported acute toxicity
was minimal with no grade 3
toxicities, 3 grade 2, 19 grade 1, and 9
patients with no acute toxicities. Additional
follow-up is needed, although
it should be noted that the dose scheme
used and volumes treated with this
technique parallel the brachytherapy
partial-breast experience, for which
acceptable late toxicity has been reported
with 5-year follow-up.[24]

Intraoperative Radiotherapy
Beyond the United States, treatment
approaches have predominantly
been intraoperative, delivering a
large single-dose fraction to the target
at the time of lumpectomy. Concerns
have been voiced regarding the
ability to properly select patients and
delineate and cover the target, and
the risk of fibrosis resulting from the
dose delivered as a large single fraction.
Despite these concerns, it is hard
to argue the attractiveness of a treatment
approach that completes all local
therapy in one trip to the operating
room. To date, the early reports from
these investigations have not described
excessive failures or soft-tissue
toxicity.[25,26]

At the University College of London,
this treatment is completed with
the placement of a soft x-ray device
into the lumpectomy cavity to deliver
21 Gy to a 2-mm depth. Intraoperative
electrons are used at the European
Institute of Oncology, where 21 Gy
is delivered to the postlumpectomy
breast tissue judged to be at risk for
failure. The target is surgically manipulated
so that it is easily encompassed
within the electron field while
temporarily pulling the skin out of the
field and placing deep shielding
to protect the underlying chest wall
and lung.

Patient Selection Criteria
and Quality Assurance

When reviewing the literature, specific
attention should be directed to
the details regarding patient selection
criteria and quality assurance guidelines
involved in the treatment experience.
In studies for which both
of these entities are clearly included,
the outcome data are consistent
and comparable to the conventional
whole-breast external-beam experience
(Table 1).[20,22-36]

Conservative patient selection criteria
have been outlined by both the
American Brachytherapy Society
(ABS) and the American Society of
Breast Surgeons (ASBS).[37,38] Both
groups agree that patients should be
older than 45 to 50 years and all cases
should first be acceptable for conventional
breast-conservation therapy.
Additional selection criteria include
primary lesions that are unifocal, small
(ABS suggests < 3 cm, ASBS recommends
< 2 cm), resected with negative
microscopic margins, and with axillary
lymph nodes evaluated and negative.

The ABS advises restricting accelerated
partial-breast irradiation to
patients with infiltrating ductal carcinoma
histology only, based on the
fact that little data exist to suggest
that additional histologies should be
included. The ASBS is in concordance
with this, but with the addition of ductal
carcinoma in situ, extrapolating
from data suggesting that wide excision
alone may be sufficient treatment.[
39] The guidelines for quality
assurance should include a target definition
of at least the lumpectomy cavity
plus a 1- to 2-cm margin, and the
methodology of treatment delivery
describing verification of the prescribed
dose to the target volume.

All three of these partial-breast
treatment approaches allow for thorough
evaluation for proper patient selection
and subsequent target
delineation and assurance of target
coverage prior to treatment delivery.
Additionally, these approaches allow
for dose delivery that is fractionated,
reducing the risk of late toxicity, ie,
fibrosis or fat necrosis.

Future Directions
Although accelerated partial-breast
irradiation is being offered in an increasing
number of facilities across
the United States, this treatment approach
has not yet been accepted as
an alternative method of local management
for early-stage breast cancer
by the entire breast oncology community.
Some physicians believe additional
data supporting the concept
of accelerated partial-breast irradiation
are needed prior to generalized
acceptance; however, it should be noted
that patients are now seeking out
locations that offer accelerated partial-
breast irradiation, and an increasing
number of physicians are offering
this treatment based on current data.

Despite the availability of 5-year
data and the acceptance of this treatment
approach, additional investigation
is necessary. Future studies should
appropriately focus on the development
of well-conducted protocols that
will further define the appropriate patient
selection criteria and continue
the development of treatment techniques.
Several phase I/II trials are
now being conducted, and many more
are in development. Additionally, a
national phase III trial which will be
jointly managed by the National Surgical
Adjuvant Breast and Bowel
Project (NSABP) and the Radiation
Therapy Oncology Group (RTOG),
has been developed and will be open
for accrual later this year.

Hypofractionated
Whole-Breast Irradiation

Reduction of treatment time to improve
patient access and maximize
availability of treatment resources has
also been the focus of study in Cana
da. In a prospective randomized trial,
investigators have demonstrated the
equivalency of two radiation treatment
schemes, thus reducing the treatment
time from 5 to 3 weeks while maintaining
the conventional whole-breast
treatment target.[40] In this trial, 1,234
patients were randomized between a
short course of radiotherapy, 42.5 Gy
in 16 fractions, and a standard course
of radiotherapy, 50 Gy in 25 fractions.
All patients were diagnosed with
T1/T2 infiltrating breast carcinoma
and resected with microscopically
negative margins. All patients were
axillary node-negative.

With a median follow-up of 69
months, they reported the observed
local recurrence rate, disease-free survival,
overall survival, and cosmetic
outcome to be equivalent. Local re-
currence rates at the time of the report
were 3.2% vs 2.8% for the standard
and short treatment courses, respectively.
Cosmetic outcome was reported
as good/excellent in approximately
75% in both treatment arms.

These results have mostly been ignored
in the United States, as there
continues to be a reluctance to adopt
this hypofractionated treatment
course. Although there has been some
level of academic discussion regarding
the possible limitations of these
data,[41] it would appear that the motivation
to change from a 6-week
course that includes a boost to a
3-week course without a boost is lacking.
The actual reasoning behind this
lack of motivation is uncertain but
may be due to the overshadowing anticipation
of accelerated partial-breast
irradiation, which will reduce the overall
treatment time to 5 days. Nevertheless,
it should be noted that the
NSABP has recently extended their
adjuvant external-beam radiotherapy
guidelines for all existing protocols to
include the Canadian hypofractionated
treatment scheme.

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