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End Results of Salvage Therapy After Failure of Breast-Conservation Surgery

End Results of Salvage Therapy After Failure of Breast-Conservation Surgery

ABSTRACT: About 10% to 15% of patients who undergo breast-conservation surgery and radiation therapy will subsequently develop ipsilateral breast tumor recurrence (IBTR). This paper reviews the biology, clinical management, and outcome of this entity. Risk factors for IBTR include young age, positive microscopic margins, gross multifocality, an extensive intraductal component, and lymphatic vessel invasion. The standard therapy following IBTR has been mastectomy, but interest in further breast-conservation approaches has recently arisen. Although the outcome following salvage therapy is quite good, the risk of distant metastases for patients with IBTR is three to five times greater than for those without recurrence. The reason for this association has been controversial, but it now appears that IBTR is both a marker of the underlying biologic aggressiveness of the tumor and a source for further tumor metastasis. Monitoring of patients following lumpectomy and radiation therapy, and aggressive therapy for IBTR when diagnosed, are clearly warranted. Prognostic factors at the time of IBTR and implications for local and systemic therapy are discussed.

Over the past 20 years, the combination
of breast-conservation
surgery and radiation
therapy has become the most common
treatment for the majority of patients
with invasive and in situ breast
malignancies. Extensive data from
both randomized trials[1-3] and large
clinical databases have shown that this
approach is equal to mastectomy in
terms of survival and provides excellent
quality of life and patient acceptance.
Nevertheless 10% to 15% of
patients treated with breast-conservation
surgery and radiation will have a
local recurrence within the ipsilateral
breast (IBTR) within 10 years.[4-8]
This paper will review the biology,
clinical management, and outcome
of patients with ipsilateral breast
recurrence.

Incidence

Each year in the United States,
there are about 200,000 new cases of
invasive breast cancer. In addition,
due to the widespread utilization of
screening mammography, the incidence
of ductal carcinoma in situ
(DCIS) has increased dramatically
over the past 20 years, and now there
are 40,000 to 50,000 new cases of
this entity diagnosed annually in the
United States. If only half of these
patients are treated with breast-conservation
therapy, and the local recurrence
rate is only 10%, that still
amounts to almost 12,000 women in
the United States who develop ipsilateral
breast recurrence each year.
That is greater than the number of
annual new cases of Hodgkin's disease
or testicular cancer. Despite these
numbers, there have been few good
prospective studies and no randomized
trials addressing treatment options
for these patients.

Table 1 shows the ipsilateral breast
recurrence rate for a variety of studies.
In the classic National Surgical
Adjuvant Breast and Bowel Project
(NSABP) B-06 trial, the recurrence
rate at 20 years was 39% for the group
that underwent lumpectomy without
irradiation and 14% for the group that
received radiation.[1] In the major prospective
randomized trial of breast
conservation from Italy, the breast recurrence
rate for the group who underwent
quadrantectomy and radiation
therapy was 8.8% at 20 years.[3] The
rate of recurrence over time in the
NSABP study is shown in Figure 1. In the group without radiation therapy,
the annual hazard rate for IBTR
was 8.5% for years 1 to 3 and then
decreased in subsequent years, whereas
in the group that received breast
irradiation, the hazard rate remained
about 1% annually throughout the follow-
up period.

Overall, the results of both prospective
randomized trials and retrospective
studies are remarkably
consistent. The IBTR rate for patients
who received partial mastectomy and
irradiation is about 5% to 10% at 5
years, 10% to 15% at 10 years, and
15% to 20% at 15 years.

Risk Factors for IBTR

Several factors have been associated
with an increased risk of IBTR.
Most studies have found that young
age, positive microscopic margins,
gross multifocality, an extensive intraductal
component (EIC), and lymphatic
vessel invasion are associated
with a higher risk of IBTR.[5,9-17] In
the Yale series, the IBTR rate was
18% at 5 years and 30% at 10 years
for women under 40, compared to 4%
and 12%, respectively, for women
over 40.[14] Similarly, a large European
study[16] found the short-term
local recurrence rate to be 10.6% for
women under 40, compared to 3.7%
for older women. The reason that
young age is associated with local
recurrence is not well understood. The
association of young age with local
relapse is not related to the primary
tumor size, nodal status, receptor status,
or other factors commonly associated
with metastatic potential.

EIC and Surgical Margin
Many studies have found gross
multifocality (ie, the presence of more
than one tumor on physical exam or
mammogram) or microscopic EIC (ie,
intraductal carcinoma occupying more
than 25% of the tumor area and extending
beyond the edge of the invasive
tumor) to be risk factors for
IBTR.[6,9,17] An EIC has been found
to be a risk factor for local recurrence
following breast-conservation surgery
but not following mastectomy, and is
not a risk factor for the development
of distant disease.[9] The presence of
EIC, however, is not a contraindication
to breast conservation, as its importance
is closely related to the extent
of surgical margin.

The definition of a satisfactory surgical
margin has been somewhat controversial.[
18] Almost all studies agree
that if there is actually tumor at the
inked margin, the IBTR rate is two to
three times higher than if the margin
is negative.[5,11,13,15,19,20] However
the significance of a "close" margin
varies in different series. It appears
that in older patients with purely invasive
tumors, just a negative margin
is sufficient, whereas in younger
women, or those with EIC, a wider
negative margin results in a lower incidence
of local recurrence. Convincing
data suggest that for pure DCIS,
the recurrence rate is inversely proportional
to the extent of the margin
up to 1 cm.[21]

Treatment
Treatment also affects the IBTR
rate. All studies agree that radiation
therapy dramatically reduces the risk
of recurrence in the breast.[1,5,6,22]
However, it is now recognized that
systemic adjuvant hormonal therapy
or chemotherapy also results in a lower incidence of IBTR.[1,9,12,19,20] The
increased use of systemic adjuvant
therapy in recent years is resulting in
a somewhat lower incidence of IBTR
than was seen in the initial trials.

Risk Model
Freedman et al[12] recently used
an interesting recursive partitioning
model to identify patients at high and
low risk for IBTR. This methodology
uses decision trees to analyze subgroups
of patients at significantly different
risk. The first split implemented
was age, with women over 55 having
different risk factors than women under
55. For women over 55, the only
other significant risk factor was
tamoxifen use. Women over 55 on
tamoxifen had a 10-year IBTR rate of
2%, compared to 5% for those not on
tamoxifen.

For women under 55, the presence
of EIC, margin positivity, tamoxifen
use, and age (< 35 vs 36 to 55) all
contributed to the definition of risk.
For example, a woman under 35 with
an EIC-negative tumor had a 10-year
IBTR rate of 3% if the margin was
negative, compared to 34% if the margin
was positive. A woman aged 36
to 55 had a 10-year IBTR rate of 5%
with tamoxifen, compared to 20%
without tamoxifen.

True Recurrence
vs New Primary

It recently became clear that a significant
portion of patients who experience
IBTR following conservative
surgery and radiation therapy actually
have new primary tumors as opposed
to true local recurrences.[9,23,24] At
Yale, Smith et al[24] defined the second
breast tumor as a new primary if
it was distinctly different from the
original tumor with respect to histologic
subtype, if it was in a different
location in the breast, or if flow cytometry
changed from aneuploid to
diploid. The time interval between the
original primary and the second tumor
was considerably greater for new
primaries compared to true recurrences
(7.3 vs 3.7 years, P < .0001). Furthermore,
10-year overall survival
(75% vs 55%, P < .0001) and distant
disease-free survival (85% vs 41%,
P < .0001) were much better for patients
with new primaries compared
to those with true recurrences.

Huang et al[23] at M. D. Anderson
also found that new primaries tended
to occur later than true recurrences,
and that overall survival and distant
disease-free survival were much better
for new primaries than true recurrences.
In addition, they found that
patients with new primaries were significantly
less likely to develop a second
recurrence following salvage
therapy (2% vs 18%, P = .008). Interestingly,
however, patients with new
primaries were more likely to develop
a new contralateral breast carcinoma
(29% vs 8%, P = .004). Therefore,
the diagnosis of a new primary as
opposed to a true recurrence clearly
implies a different natural history and
prognosis, and has different implications
for therapeutic management.
Unfortunately, most series addressing
IBTR do not adequately distinguish
between the two.

Differentiating between a new primary
and a true recurrence is particularly
valuable in understanding the
biology of breast cancer in young
women with BRCA1/2 mutations.
Although early results have indicated
acceptable results with breast conservation
in this population, more prolonged
follow-up has revealed a continued increased incidence of IBTR
due to new primaries, as well as an
increased incidence of new contralateral
breast cancers.[25] Further study
of this group using chemoprophylaxis
or bilateral mastectomy is warranted.

Treatment Options for IBTRMastectomy
Most patients with IBTR have undergone
salvage therapy with mastectomy,
and this has been considered
the standard treatment.[26-30] Mastectomy
generally results in long-term
local control rates of 85% to 95% and
10-year overall survival of 60% to
70%. In an early study of mastectomy
for IBTR, Fowble et al[28] achieved
local control in 95% of patients; at
5 years, the overall survival rate was
84% and distant disease-free survival
was 59%. The authors could not identify
any factors that would predict for
no disease in the mastectomy specimen,
so they recommended mastectomy
as the preferred treatment. In
another early study, Kurtz et al[31]
noted locoregional control in 88% at
5 years following salvage mastectomy,
and in only 64% after further
breast-conserving salvage procedures,
although the type of salvage operation
did not affect survival.

In more recent reports, Dalberg et
al[32,33] studied the incidence of uncontrolled
local disease, defined as
the appearance of cancer in the remaining
breast or chest wall that could
not be eradicated within 3 months by
further treatment. The cumulative incidence
of uncontrolled local disease
at 5 years following salvage mastectomy
was 12%, compared to 33% after
salvage reexcision. Development
of uncontrolled local disease was a
very grave prognostic sign: Indeed,
78% of such patients died of disseminated
breast cancer, compared to only
10% of patients with IBTR who were
salvaged without further local recurrence.
Certainly this is one of the
strongest arguments for using mastectomy
to salvage patients with IBTR.

Reconstruction
If mastectomy is necessary, it
would certainly be helpful to be able
to offer patients breast reconstruction.
Unfortunately, there have been only a
few studies of breast reconstruction
following IBTR. Forman et al[34] reported
on 10 breast reconstructions
using tissue expanders and implants
after salvage mastectomy for IBTR.
Unfortunately one implant extruded,
another became infected, two did not
expand because the irradiated tissue
lacked compliance, and two more developed
severe capsular contractures.
Overall, 60% of the patients had a complication
or an unfavorable result.

Most plastic surgeons probably
prefer autogenous tissue reconstruction
in patients who have received
breast irradiation. However even pedicled
transverse rectus abdominis myocutaneous
(TRAM) flaps have been
reported to have complication rates
of up to 33% in irradiated tissue beds.
Moran et al[35] reported on 14 patients
who underwent free TRAM
flaps with anastomosis to the thorocodorsal
vessels. Their complication
rate was only 14%, and the aesthetic
result was rated as excellent.

Repeat Lumpectomy With or
Without Additional Radiation

Although mastectomy has been
considered the standard therapy for
IBTR, there is increasing interest in
defining a patient population for
whom breast preservation may be appropriate.
In a large study of 197 patients
with operable IBTR, Salvadori
et al[36] treated 70% with mastectomy
and 30% with further local resection.
A second IBTR was more
common at 5 years in the reexcision
group (19% vs 4%), but there was no
difference in disease-free survival.
Because the type of surgery did not
affect survival, the authors concluded
that breast conservation can be considered
in selected patients with IBTR.

Komoike et al[37] treated 30 IBTR
patients with repeat lumpectomy. Nine
of these patients developed a second
local relapse, but those who did not
tended to have small tumors (< 1 cm) with a low histologic grade and no
lymphatic invasion. In contrast, those
who failed this therapy tended to be
young (age < 35), to have positive
family histories, and to not receive
adjuvant systemic treatment.

The literature contains some experience
with a second course of radiation
therapy following local resection
of an IBTR. Deutsch et al[38] treated
39 women who had had repeat
lumpectomy for IBTR with 5,000 cGy
to the operative area using electrons.
The treatment was well tolerated, and
the only late sequelae were skin pigmentation
changes. Nine (23%) of
these patients developed a second
IBTR. The overall and disease-free
survival of the entire group at 5 years
was 78% and 68%, respectively.
Resch et al[39] treated 17 IBTR patients
with pulse dose-rate brachytherapy
following repeat lumpectomy.
Twelve did not develop further breast
recurrence, and side effects were limited
to moderate (grade 1/2) fibrosis.
Both authors concluded that repeat
radiation therapy may be an acceptable
alternative to mastectomy for selected
patients.

Systemic Adjuvant Therapy
IBTR is a strong independent predictor
for the subsequent development
of distant disease. For that reason, several
authors have recommended adjuvant
systemic therapy at the time of
IBTR,[40,41] and many oncologists
use this strategy based on extrapolation
of the data for adjuvant treatment
of primary breast cancer. Unfortunately
there are no published prospective
trials addressing the issue.[42] There
is one prospective randomized trial of
hormone therapy in 167 patients with
chest wall recurrence following mastectomy.[
43] Tamoxifen was found to
significantly increase 5-year diseasefree
survival from 36% to 59% compared
to placebo, but there was no
improvement in overall survival. One
recent retrospective study of IBTR following
lumpectomy found a benefit
for ovarian suppression and chemotherapy
at the time of IBTR in premenopausal
patients but not in
postmenopausal patients.[44] Clearly
more studies are needed.

The International Breast CancerStudy Group recently initiated a randomized
trial of adjuvant chemotherapy
following IBTR, and the NSABP
plans to collaborate and open the trial
in the United States.[45] This would
seem to address an important clinical
question, and hopefully answers will
be forthcoming.

Outcome of Treatment of IBTR

Table 2 shows the overall survival
and disease-free survival following
treatment of IBTR in several series.
The overall survival averages 74% at
5 years and 65% at 10 years; and the
disease-free survival averages 60% at
5 years and 57% at 10 years. When
these data first became available more
than a decade ago, it was impressive
that the prognosis for patients following
IBTR was so favorable, particularly
when compared to that of patients
who developed chest wall recurrence
following mastectomy. The overall
5-year survival for patients with chest
wall recurrence averaged 35%, with
disease-free survival of 30%. Clearly,
salvage following IBTR produced survival
rates that were about twice as
high.[5] Therefore, it became accepted
that patients need to be followed
closely following lumpectomy, so that
if IBTR developed, it could be detected
early and the patient would still
have a good chance of cure with salvage
therapy.

When considering survival for patients
with IBTR, it is important to
note whether that parameter is measured
from the date of the IBTR, or
from the date of diagnosis of the original
tumor. Although, as mentioned
above, the survival measured from
the date of IBTR is relatively good, if
we examine survival from the date of
original diagnosis in patients who do
or do not develop IBTR, it is clear
that IBTR is a strong independent risk
factor for the development of distant
metastases.

Most studies have found that the relative
risk of distant metastases with
IBTR ranges from three- to fivefold.[
19,20,40,46-50] For example, in
the NSABP B-06 study,[40] the risk
of distant disease was 3.41 times greater
in patients who developed an IBTR,
even when adjusted in multivariate
analysis for all other prognostic variables,
such as patient age, nodal status,
nuclear grade, tumor type, and maximum
pathologic tumor size. IBTR is
actually one of the strongest prognostic
variables available to predict distant
metastases or death from breast
cancer. The interpretation of this association,
however, has varied widely.

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