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282 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
TABLE 18–3Taxanes in the
Neoadjuvant Setting
Study Regimen Breast-
Conservation
Therapy rate (%)
Geparduo APx4 q2W 66
ACx4 ! Tx4 75
Geparduo TACx6 81
AGO ETx4 55
Ex3 ! Tx3, q2W 66
NSABP B-27 ACx4 62
ACx4 ! Tx4 64
A, doxorubicin; C, cyclophosphamide; E, epirubicin;
P, paclitaxel; T, docetaxel.
surgery. Ongoing prospective clinical trials will
better define which aromatase inhibitor (if any)
mightbe best and providevaluableclinical information regarding the clinicaluse of neoadjuvant
hormonal therapy on downstaging tumors.
Future trials directly comparing neoadjuvant
hormonal therapy to neoadjuvant chemotherapy are planned.
Most neoadjuvant therapy consists of cytotoxic chemotherapy. Anthracycline-based regimens are the most extensively studied, and the
typical neoadjuvant approach consists of four to
six cycles of Adriamycin and cyclophosphamide.
More recent data demonstrate a higher clinical
and pathologic response rate with the addition
of a taxane, and four cycles of Adriamycin/cyclophosphamide followed by four cycles of taxol
have become a common neoadjuvant regimen
(Table 18–3). For patients who are human epidermal growth factor receptor 2 (Her-2/neu) positive, even higher response rates may be
achieved with the addition of Herceptin.
Although a wide variety of timing schedules have
been studied, there is no consensus on whether
sequential, concurrent,or dose-dense approaches
should be considered the standard of care.
do not directly benefit from the chemotherapy
being delivered before surgery as compared to
after surgery, although giving neoadjuvant
therapy may give the patient time to consider
reconstructive options or contralateral mastectomy, and the tumor response may yield prognostic information. Likewise, patients who
would not require adjuvant chemotherapy
(based on their risk of distant disease) should
not be given neoadjuvant chemotherapy simply
to downstage their primary tumor. The indications for chemotherapy should be clear. For
example, some patients with large-volume, palpable ductal carcinoma in situ (DCIS) may
require a mastectomy based on the size of the
tumor, but clearly do not merit chemotherapy,
and thus neoadjuvant chemotherapy is contraindicated. It is important, however, to confirm that
they have only DCIS or DCIS with microinvasion
and not a large invasive component. If this cannotbedonewithmultiplecore-needlebiopsies,
an open, incisional biopsy may be necessary.
Recommendations for neoadjuvant chemotherapy may also be based on the likelihood of
downstaging occurring. Hormone receptor status, Her-2/neu status, tumor grade, primary
tumor histology, and patient age are factors that
may influence this. ER/PR-positive, low-grade
tumors are less likely to decrease in size than
ER/PR-negative or high-grade tumors. Compared with ductal carcinoma, lobular carcinoma
tends to present at a more advanced stage and is
less likely to respond to neoadjuvant therapy.
These women have lower rates of breast conservation after neoadjuvant therapy than women
with ductal carcinoma,and although thisshould
be discussed with the patient with lobular carcinoma, it is not an absolute contraindication to
neoadjuvant chemotherapy.
Neoadjuvant Chemotherapy and Surgery
Patient Selection for Neoadjuvant Therapy
As stated, the primary indication for delivering
chemotherapy in the neoadjuvant setting is to
downstage the primary tumor to increase the
likelihood of successful breast conservation.
Patients who will require mastectomy regardless of response, such as those with multicentric disease, widespread calcifications, or
those who cannot undergo radiation therapy,
Breast Conservation Rates
The National Surgical Adjuvant Breast and Bowel
Project (NSABP) B-18 trial was the first and largest study to compare delivery of chemotherapy
before surgery, with postoperative chemotherapy . This trial found that although doxorubicin
and cyclophosphamide (four cycles) given preoperatively did not improve survival, there
was a 7% higher rate of breast conserving surgery (p < 0.01). Other trials confirmed these
results, although they varied in the eligibility criteria and the regimen of chemotherapy. Using
Concentric
28318—NEOADJUVANT THERAPY
Figure 18-1. As with a lollipop
beinglicked, chemotherapy may
shrink the tumor concentrically,
toward a smaller central mass
but leaving no disease at the
periphery. A smaller area of resectionis appropriate.However,
if the tumor shrinks in a way
that leaves microscopic satellite lesions, the same area of
resection as before chemotherapy may be needed.
Honeycombed
four cycles of fluorouracil, epirubicin and cyclophosphamide (FEC), both the Institute Curie
and the European Organization for Research
and Treatment of Cancer (EORTC) reported
increased rates of breast conservation with preoperative chemotherapy (5% and 16% increases,
respectively).
Using improved combinations or sequences
of drugs, the breast conservation rate can
be further increased. The European Cooperative Trial (ECTO) compared preoperative or
postoperative doxorubicin and paclitaxel in
combination, followed by four cycles of
cyclophosphamide, methotrexate, and fluorouracil (CMF). In this study, the breast-conserving surger y rate increased from 34% to
65%. Subsequent studies confirmed that the
response rates and breast-conserving surgery
rates could be further improved by adding
taxanes to the combination. The NSABP
B-18 trial had a pathologic complete response
rate of 9.8%. This is substantially higher in
studies using taxanes (GEPARDUO-22%;
AGO-18%; NSABP B27-26%).
Local Recurrence Rates after Neoadjuvant Chemotherapy
The primary indication for neoadjuvant chemotherapy, outside of a clinical trial, is to downsize the primary breast tumor, facilitating a
margin-negative lumpectomy with a smaller
volume. However, there are two ways the
Allows for decreased
volume of resection.
Requires the same
volume of resection as
before chemotherapy
tumor may shrink (Fig. 18–1), often compared
to either a lollipop or a dandelion. As with a lollipop being licked, the tumor may shrink down
concentrically, toward a smaller central mass
but leaving no disease at the periphery.
This would lend itself quite well to a reducedvolume lumpectomy. However, if the tumor
shrinks in a way that leaves microscopic satellite
lesions, then breast conservation may be compromised. This honeycombed response has
been compared to blowing on a dandelion to
completely rid it of its seeds. The tumor disappears in a more scattered pattern, leaving microsatellite lesions anywhere within the original
tumor volume. After lumpectomy, this would
result in a high rate of margin failure and local
recurrence rates.
Of the major randomized studies of neoadjuvant chemotherapy, local recurrence rates
have been either equivalent or higher in the
preoperative chemotherapy arms, but within
acceptable limits (Table 18–4). Local recurrence rates varied between 3% and 27% and
depend on the duration of follow-up, the type
of surgery, and the margins obtained. The
largest study, NSABP B-18, randomized over
1500 women with stages I through IIIA breast
cancer to preoperative or postoperative chemotherapy. There was a statistically significant
increase in breast conservation (68% versus
60%), but with a median follow-up of 72
months, there was no statistically significant
difference in local recurrence following BCT
284 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
TABLE 18–4Local Recurrence Rates After Neoadjuvant Chemotherapy
Overall Survival Local Recurrence
Study Patients Median Follow-Up
Institut
Bergonie
Institut Curie 414 66 86 78 24 18
Royal
Mardson
NSAPB B18 1523 108 69 70 10.7 7.6
NSAPB, National Surgical and Adjuvant Breast Project.
272 124 55 55 23 NA
309 48 80 80 3 4
(Months)
(7.9% versus 5.8%). However, this includes
those patients who were candidates for lumpectomy before they received their chemotherapy. If you look at just those patients
who would have required mastectomy, but
were downstaged to become eligible for BCT,
there was a higher local recurrence rate. The
rate of local recurrence in patients who had
BCT after neoadjuvant chemotherapy instead
of mastectomy was 16% compared to the
10% of patients who were considered candidates for BCT before chemotherapy. It is hard
to say how significant this increase in local
recurrence this was, because most of these
were T3 tumors and would have had an
increased rate of chest wall recurrence if mastectomy would have been performed.
Preoperatively (%)
Postoperatively (%)
Preoperatively (%)
Postoperatively (%)
surgeon should assure that precise localization
will still be possible when the chemotherapy is
completed. Several methods have been proposed for this. One option is to mark on the
skin of the patient the exact location and size
of the tumor and the proposed surgical skin
incision and then photograph this. The boundaries of the tumor can also be marked on the
skin with small tattoos, similar to the tattooing
done for radiation therapy. The most common
method is to place a metal clip or coil in the
center of the lesion. In the patient who had a
core biopsy of a palpable mass performed in
the office, this may require an additional procedure. However, this will be well worth it if there
is complete clinical resolution of the mass. With
improving chemotherapeutic regimens, a complete clinical response is becoming more
Primary Surgery after Neoadjuvant Chemotherapy
When neoadjuvant chemotherapy was first
proposed, there was some concern that this
might increase the rate of surgical complications or radiation side effects. After 30 years
of experience, this has not been seen and
should not be a concern. Surgery should not
be performed until leukocyte counts and
hemoglobin and hematocrit levels are back
to normal, which typically takes 3 to 4
weeksafterthelastcycleofchemotherapy
(although it may take up to 6 wee ks in some
patients).
The goal of the chemotherapy is to shrink the
primary tumor to allow for breast conservation.
Hopefully, the tumor will completely disappear
because a complete pathologic response is associated with an improved OS. The surgeon therefore needs to plan on the possibility that at the
time of surgery, there will be no way of identifying where the primary tumor was. Therefore,
before the initiation of chemotherapy, the
frequent.
When the decisionis made to use preoperative
chemotherapy, it is accepted that surgery is an
obligatory part ofthe multidisciplinaryapproach
to the tumor. However, after a complete clinical
response, patients often question why they still
need to undergo surgery. It is important to
inform patients that even when there is a complete disappearance of the tumor on physical
examination, mammography, or ultrasound,
there remains uncertainty whether there is
microscopic disease still in the region. Therefore,
lumpectomy is still required to assess the pathologic response. Although some studies have suggested magnetic resonance imaging (MRI) may
be more accurate for assessment of residual disease, it is still not reliable enough to avoid lumpectomy. Likewise, the presence of a residual mass
does not always mean that a complete pathologic response has not been achieved because it
may not be possible to differentiate chemotherapy-induced fibrosis from tumor.
A careful physical examination should be
performed to document the extent of disease
28518—NEOADJUVANT THERAPY
in both the breast and regional lymph nodes.
This should be accompanied by repeat imaging studies including mammography and
ultrasound. MRI should only be used if it was
also used preoperatively. The surgeon must
decide whether the residual mass may be
excised with a satisfactory cosmetic result and
negative margins. The geography of the residual mass, the shape and size of the breast,
and the presence of microcalcifications will
influence this decision. Malignant-appearing
calcifications do not always resolve with
chemotherapy, and if there remain large areas
of calcifications on the postchemotherapy
mammogram, these must be incorporated in
the lumpectomy. Patients who began with
locally advanced cancer should have regression of any skin or chest wall involvement.
Patients who began with inflammatory carcinoma should undergo mastectomy regardless
of their clinical response.
When the surgeon takes the patient to the
operating room, they are faced with a question
of how much tissue to remove. Obviously, if
the tumor was large enough to warrant a mastectomy, then using the original tumor size to
guide the excision would preclude breast conservation and obviate the need for having
delivered the chemotherapy upfront. However, there may be no macroscopic evidence
of disease to guide the surgeon in how much
tissue to remove. What about the patient
who was a candidate for a lumpectomy before
neoadjuvant chemotherapy? Should the lumpectomy be guided by the size of the present
tumor, or should the extent of excision
be based on the original size of the tumor?
Within the limits of aesthetics, the wider margins the better (with an optimum margin of
1 cm). Reducing the volume of tissue will
increase the likelihood of reexcision; however,
this can often still successfully clear the margins satisfactorily. The balance between the
oncologic resection and the cosmetic outcome
is a decision for the surgeon and patient, but
should tilt toward the former.
Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy
Before the introduction of sentinel lymph node
(SLN) biopsy as a method of staging the axilla,
there was little impact surgically on whether
patients received neoadjuvant chemotherapy
or not because either way they would be receiving an axillary lymph node dissection (ALND).
The most significant impact of preoperative
therapy was that there were some patients
who may have been node positive initially but
were node negative after chemotherapy and
so their true nodal status remained unknown.
This did not alter their surgery, and at the time
there was less impact of nodal status in guiding
radiation therapy.
This changed dramatically as lymphatic
mapping and SLN biopsy became standard in
the surgical therapy of breast cancer. Now
patients who opted for neoadjuvant chemotherapy to shrink their primary tumor were
obligated to undergo ALND as part of their surgery, whereas if they had surgery first, they
could opt for an SLN biopsy and avoid ALND
if they were node negative. In addition, the
nodal status plays a larger role in therapy decisions. Some medical oncologists would reserve
the use of taxanes or dose-dense regimens
for patients they know to be node positive.
The use of postmastectomy radiation for
patients who are node positive has become
more prevalent. These practices made it more
important to know whether the patient was
node positive. Thus the question arose of how
to best integrate SLN biopsy with neoadjuvant chemotherapy for clinically node-negative
breast cancer.
SLN biopsy is only necessary in patients
who are clinically node negative. Patients with
palpable disease in the lymph nodes can have
this confirmed by fine-needle aspiration
(FNA) and proceed with neoadjuvant chemotherapy with a planned ALND at the completion of systemic therapy. Patients who are
clinically node negative should have an ultrasound of the axilla looking for abnormal
lymph nodes. Ultrasound-guided FNA can
then document these patients to be node positive before neoadjuvant chemotherapy. For
patients who are clinically and ultrasonographically node negative, there are two options
for the use of SLN biopsy if they are candidates
for neoadjuvant chemotherapy.
The first option is to perform the SLN biopsy
before beginning chemotherapy. There are several advantages to this approach. The first is
that the true nodal status is known before initiating chemotherapy, which may be important
if this will help decide what regimen and schedule to use. Likewise, this will help the radiation
oncologist decide whether they would recommend postmastectomy radiation should the
patient not be a candidate for BCT. However,
there are several factors that go into this decision, including the size of the primary tumor.
286 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
BOX 18–3 ADVANTAGES AND DISADVANTAGES OF SENTINEL LYMPH
NODE BIOPSY BEFORE OR AFTER NEOADJUVANT CHEMOTHERAPY
Advantages Disadvantages
Before
chemotherapy
After
chemotherapy
Higher identification rate
Likely lower false-negative rate
Accurate pretherapy nodal staging
No need for surgery before
chemotherapy
No axillary lymph node dissection
performed on patients who become
node negative
Requires an additional surgery
Delays the beginning of chemotherapy
May subject patients converted to node
negative to an unnecessary axillary
lymph node dissection
Slightly lower identification rate
Higher false-negative rate
Will mislabel some patients who were
initially node positive as node negative
If the nodal status would not change either the
medical oncologists’ or radiation oncologists’
recommendations, then knowing the prechemotherapy nodal status becomes less important.
This emphasizes the importance of presenting
these patients at a tumor board and formulating a treatment plan in a multidisciplinary
setting.
Another advantage to performing SLN biopsy
before chemotherapy is the confidence in the
feasibility and accuracy of the procedure. There
has been some concern that the chemotherapy
may affect the lymphatic drainage and make
identification of the SLN more difficult. In addition, performing SLN biopsy after chemotherapy supposes that if there was disease in the
lymph nodes it will either completely disappear
from all the nodes, or if not, it will remain in
the sentinel node. However, if it is eradicated
from the sentinel node, but not the nonsentinel nodes, this will lead to a false-negative
finding. Unfortunately, performing SLN biopsy
before the onset of chemotherapy means an
extra procedure and a delay in the initiation
of therapy (Box 18–3).
The second option is to perform the SLN
biopsy after completing chemotherapy. This
presumes that it is accurate to do so. Several
studies of SLN biopsy after neoadjuvant chemotherapy have been performed, and although
some have suggested an unacceptably high
false-negative rate, overall this seems to be reasonable (Table 18–5). Although a clear disad-
vantage of this approach is not knowing the
true nodal status, if this would not impact
the chemotherapy decisions, this is less of a
factor. In regard to postmastectomy radiation,
some might argue that the nodal status after
chemotherapy might serve as a better indicator of whether to offer radiation to the
chest wall. Delaying the SLN biopsy to after
chemotherapy also allows the chemotherapy
to start immediately and may preclude the
need for an additional surgery. The most
important advantage to SLN biopsy after chemotherapy is that patients who may have
been node positive before chemotherapy,
but are now node negative, will be spared
from ALND. Approximately 20% of patients
may be converted from node positive to node
negative, and the use of SLN biopsy before
chemotherapy would obligate those patients
to undergo ALND. Future clinical trials will
TABLE 18–5Success Rates and False-
Negative Rates of Sentinel Lymph Node
Biopsy After Neoadjvuant
Chemotherapy
Author Patients Sentinel
Lymph Node
Identification
Rate (%)ate
Breslin 81 85 12
Nason 15 87 33
Haid 33 88 0
Fernandez 40 90 20
Tafra 29 93 0
Stearns 26 88 6
Julian 34 91 0
Miller 35 86 0
Brady 14 93 0
Piato 42 98 17
Balch 32 97 5
Schwartz 21 100 9
Reitsamer 30 87 7
Mamounas 428 85 11
TOTAL 87 9
FalseNegative
Rate (%)
28718—NEOADJUVANT THERAPY
better define the timing of SLN biopsy with
neoadjuvant chemotherapy.
Neoadjuvant Chemotherapy and Outcome
Does Earlier Delivery of Chemotherapy Improve Survival?
The ultimate danger of breast cancer is not
the primary tumor, but rather the ability of
breast cancer metastases to cause vital organ
dysfunction. Therefore, the persistence of distant micrometastases through systemic therapy is ultimately what will determine survival
after treatment. The original hypothesis of
neoadjuvant chemotherapy was that instead
of delaying systemic therapy until after surgery, the earlier initiation might do a better
job of eradicating these micrometastases. There
are animal studies to suggest that after resection of the primary tumor, an increase in the
growth rate of micrometastases is seen. The
explanation for this is unclear, possibly related
to inhibitory factors released by the primary
tumor or an immunosuppressive effect of surgery. However, these studies show that preoperative chemotherapy can prevent this growth
spurt. This survival advantage to neoadjuvant
chemotherapy for operable breast cancer, however, has not been borne out by any of the randomized trials, all of which had equivalent
survivals between preoperative and postoperative chemotherapy.
Can Neoadjuvant Chemotherapy Be Used as a Chemosensitivity Test?
A pCR is defined as the complete absence of
residual invasive and in situ disease following neoadjuvant chemotherapy and surgery,
although some have defined a complete
absence of invasive disease, even in the presence of in situ disease, as a pCR. Although
the studies failed to show any difference in
OS or DFS between preoperative and postoperative chemotherapy, they did demonstrate a
correlation between the response of the tumor
to chemotherapy and the outcome. For example, in the NSABP B-18 trial, patients who had
a complete clinical response had an overall
survival of 78%. This dropped to 67% for
patients with a partial clinical response and
65% for patients with no clinical response.
The correlation between response and outcome is independent of tumor size, nodal
status, or age. A better predictor of outcome
than clinical response is pathologic response.
At 9 years of follow-up, the OS of patients
who achieved a pCR was 85%, compared to
73% for patients with residual cancer.
In addition to downstaging the primary
tumor, the status of the regional lymph nodes
is also downstaged. Patients who have a pCR
in the breast are more likely to have a pCR in
the axillary lymph nodes as well, although
not always. Kuerer and others, from the MD
Anderson Cancer Center, found that of the
16% of patients who had a pCR in the primary
tumor, 75% alsohad a pCR in the axillary nodes.
Rouzierand others reported thatof patientswith
documented disease in the regional nodesbefore
chemotherapy, a pCR in the axillary nodes was
associated with a significantly better 5-year
DFS. The effect in the nodes may be a better
marker of outcome than the effect on the primary tumor. In the NSABP B-27 trial, patients
who received a pCR in the breast, but still had
residual disease in the nodes, had a similar outcome with those patients who did not receive a
pCR in the breast. This suggested that the
responsein the nodes may be the strongest prognostic factor. This makes biologic sense because
distant micrometastases (whose ablation ultimately defines overall survival) are probably
more similar to nodal metastases than the primary tumor.
Knowing that a pCR in the primary tumor
and axillary nodes is associated with a significantly improved outcome, how can this information be used? The potential for research is
evident. Without neoadjuvant chemotherapy,
the only way to assess a new systemic therapy
is to perform a prospective randomized trial
comparing the new agent to standard chemotherapy and looking at DFS or OS. This takes
many patients and will take several years to
provide an answer. In the neoadjuvant setting,
new systemic therapies can be delivered before
surgery, with pathologic response as the endpoint. This takes considerably less patients
and can be concluded in a matter of months.
In addition, the use of neoadjuvant therapy,
with the ability to obtain tumor specimens
before and after chemotherapy, allows for the
investigation of molecular markers for prediction of tumor response.
Does this benefit individual patients? In
other words, is there a benefit to the patient
to assess in vivo their individual response to
the chemotherapy? Patients showing a poor
response to therapy can have ineffective
chemotherapies stopped, avoiding unnecessary
288 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
toxicity. They can then opt to proceed with
surgery or try a different agent.
What about the patient who completes their
chemotherapy and undergoes surgery but is
found to have only a partial response? As
patients with residual disease in either the
breast or axillary lymph nodes are known to
have a poorer outcome compared with those
who have a pCR, does this mean that these
patients should receive additional chemotherapy with a new agent after surgery?
Achieving a pCR is clearly associated with
better outcome but does the response rate
translate into better DFS and OS? In other
words, if you can increase the pCR rate (perhaps by changing drugs or treating for more
cycles) will this translate into improved outcome? The NSABP B-27 trial hoped to answer
this. Patients were randomized into three
groups. The first group received preoperative
doxorubicin/cyclophosphamide (AC). The second group received preoperative AC, had surgery, and then received postoperative
docetaxel. The third group received AC and
docetaxel before surgery. As expected, the addition of taxanes increased the pCR rate. Arms 1
and 2, which had AC before surgery, had pCR
rates of 12.8% and 14.3%, respectively. Arm 3,
which had preoperative AC and docetaxol,
had a pCR rate of 26%. In all three groups, a
pCR was associated with a significantly
improved outcome compared to patients who
did not achieve a pCR. However, all three
groups had the same OS. Perhaps the increase
in pCR rate was not sufficient enough to translate to a statistically significant improvement
for the entire group. Unfortunately, without a
difference in survival, the trial could not answer
whether patients who did not achieve a pCR
with AC received any survival benefit to the
addition of docetaxel. To date, therefore, no
data exist in the literature to guide clinicians,
and so decisions about further systemic therapy
must be made on an individual patient basis.
If it were demonstrated that patients who
do not receive a pCR benefit from additional
systemic therapy, then the indication for
neoadjuvant chemotherapy as a “chemosensitivity test” would argue for the expanded use
of chemotherapy before surgical intervention,
even in patients for whom breast conservation
is feasible. However, there may be additional
markers that can be used besides pCR. The
search continues for new molecular markers
of response through the use of proteomics,
microarray analysis, and immunohistochemical staining. It may be feasible in the future
to analyze the tumor during or after chemotherapy to determine whether the regimen
should be altered or if additional therapy is
needed after surgery.
Suggested Readings
1. Bear HD, Anderson S, Brown A, et al. The effect on
tumor response of adding sequential preoperative
docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol
B-27. J Clin Oncol 2003;21:4165–4174.
2. Beresford M, Padhani AR, Goh V, et al. Imaging
breast cancer response during neoadjuvant systemic
therapy. Expert Review of Anticancer Therapy
2005;5(5):893–905.
3. Kaufmann M, von Minckwitz G, Smith R, et al.
International expert panel on the use of primary
(preoperative) systemic treatment of operable breast
cancer: review and recommendations. J Clin Oncol
2003;21:2600–2608.
4. Khan A, Sabel MS, Nees A, et al. Comprehensive axillary evaluation in neoadjuvant chemotherapy
patients with ultrasonography and sentinel lymph
node biopsy. Ann Surg Oncol 2005;12(9):697–704.
5. Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and
impact of documented eradication of breast cancer
axillary lymph node metastases before surgery in
patients treated with neoadjuvant chemotherapy.
Ann Surg 1999;230:72–78.
6. von Minckwitz G, Costa SD, Raab G, et al. Dose-dense
doxorubicin, docetaxel, and granulocyte colonystimulating factor support with or without tamoxifen
as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open
phase IIb Study. J Clin Oncol 2001;19:3506–3515.
7. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast
cancer: nine-year results from National Surgical
Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001;30:96–102.
19
Locally Advanced and Inflammatory Breast Cancer
LOCALLY ADVANCED BREAST
CANCER
Diagnosis and Workup of
Locally Advanced Breast
Cancer
Treatment of Locally Advanced
Breast Cancer
INDUCTION CHEMOTHERAPY
Local Surgery after Induction
Chemotherapy
Locally Advanced and Inflammatory Breast
Cancer: Key Points
Define locally advanced breast cancer.
Describe the workup and staging of the patient presenting with
locally advanced breast cancer.
Know the benefits of induction chemotherapy in the management of locally
advanced breast cancer.
Understand the clinical presentation and diagnosis of inflammatory breast
cancer.
Describe the treatment algorithm for inflammatory breast cancer, including
the surgical management.
Regional Surgery after Induc-
tion Chemotherapy
INFLAMMATORY BREAST
CANCER
Diagnosis and Workup
Treatment of Inflammatory
Breast Cancer
With the promotion of breast self-examination
(BSE) and screening mammograms, the average size at which breast cancer is detected have
been steadily decreasing. Some women, unfortunately, will either not be diagnosed or will
not seek treatment until the breast cancer is
more advanced. This is generally referred to as
locally advanced breast cancer (LABC) and
continues to represent a significant burden.
This is especially true in areas where access to
289
290 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
screening and adequate health care is limited.
Today, in the United States, approximately
5% of patients that are newly diagnosed with
breast cancer have LABC. Worldwide, however,
LABC is the most common presentation of
breast cancer. For example, in India, the number of patients with breast cancer presenting
with LABC may be as high as 50% to 70%.
Locally Advanced Breast Cancer
The definition of LABC has changed over the
years. Originally, the term referred to patients
who had features associated with a high chance
of local recurrence and low chance of cure after
radical mastectomy. These included significant
skin involvement or satellite nodules in the
skin, lymphedema of the arm, internal mammary or supraclavicular metastases, chest wall
fixation, or large axillary lymph nodes. These
types of observations ultimately led to more
formal staging systems based on prognosis.
In general, LABC is defined as either large,
bulky primary tumors or extensive adenopathy.
Patients with American Joint Commission on
Cancer (AJCC) T3 or T4 tumors (associated with
chest wall fixation, skin ulceration, or both) are
classified as LABC. Also classified as LABC are
patients with AJCC N2 or N3 disease (matted
axillary nodes, supraclavicular or internal mammary metastases; Ta b l e19–1).
Inflammatory breast cancer (IBC) is distinct
from LABC and will be discussed later in the
chapter. IBC should be considered separately
from LABC because it has a distinct biologic
behavior. However, because it is staged as T4d,
it has been included in series of LABC cases.
Whether to include AJCC T3 tumors (tumors
> 5 cm) as LABC has also been controversial
because although T4 lesions are generally inoperable, T3 tumors are generally operable, albeit
by mastectomy. Finally, ipsilateral infraclavicular or supraclavicular nodal involvement used
to be considered metastatic disease, so many
older series of LABC would not include these
patients. However, the updated AJCC staging
system includes these patients as having N3 disease based on the fact that these patients can
achieve long disease-free survival (DFS) and
potentially be cured. Therefore, more recent
series of LABC will include these patients.
However one defines LABC, this group of
patients clearly represents a subset of patients
with more advanced disease. Whether this is as
TABLE 19–1American Joint
Committee on Cancer Staging for
Locally Advanced Breast Cancer
Stage Primary
Tumor
IIB T3 N0
IIIA T0 N2
T1 N2
T2 N2
T3 N1
T3 N2
IIIB T4 Any N
Any T N3
T3, Tumor more than 5 cm in greatest diameter.
T4a, Extension to chest wall, not including pectoralis
muscle.
T4b, Edema or ulceration of skin or satellite nodules
confined to same breast.
T4c, Both T4a and T4b.
T4d, Inflammatory carcinoma.
N1, Movable, ipsilateral lymph nodes.
N2, Fixed or matted ipsilateral axillary nodes or
clinically apparent ipsilateral internal mammary
nodes.
N3, Metastasis in ipsilateral infraclavicular or
supraclavicular lymph nodes or in clinical apparent
internal mammary nodes and clinically evident
axillary node metastases.
Regional Lymph
Nodes
a result of neglect and delayed diagnosis or a
more aggressive tumor biology is not completely
understood, nevertheless a more aggressive
approach to therapy will be necessary.
Diagnosis and Workup of Locally Advanced Breast Cancer
The diagnosis of LABC is relatively straightforward. By definition, patients present with
either a large, firm, fixed palpable mass or large
or matted lymph nodes (Fig. 19–1). As with all
women with a suspicious breast mass, workup
includes diagnostic imaging (mammography,
ultrasound and possibly magnetic resonance
imaging [MRI]) and tissue biopsy. If there is
no palpable adenopathy, an ultrasound of the
axilla should be performed, with fine-needle
aspiration (FNA) biopsy of any abnormal
lymph nodes. If patients present with multiple
or matted lymph nodes, but no identifiable
mass in the breast on either physical examination or mammogram (and possibly wholebreast ultrasound), an MRI should be obtained
to look for an occult breast cancer.
The breast imaging should be carefully
reviewed for other abnormal lesions. If present,
30% for LABC. The metastatic workup should
include laboratory work, bone scan, and computed tomography (CT) scans of the chest,
abdomen, and pelvis. Positron emission tomography (PET) scan is being investigated as a
staging examination, and although it should
not serve as a substitute for these other studies,
it may serve as a useful adjunct. MRI of the brain
is only indicated when central nervous system
symptoms are present. Even with the advanced
nature of their primary disease, the majority of
patients with LABC will have no evidence of
distant disease.
29119—LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCER
Figure 19–1. Locally advanced breast cancer.
biopsy of these additional lesions is necessary
because the identification of multicentric disease
would preclude breast conservation therapy
(BCT) after chemotherapy. Likewise, the identification of multicentric disease or diffuse calcifications before chemotherapy should prompt a
discussion with the patient regarding the need
for mastectomy regardless of degree of response
to the chemotherapy. In this way, there are no
surprises or mixed messages, and the patient
has time during the chemotherapy to come to
terms with the need for mastectomy. Likewise,
there may be time for genetic counseling and
testing, and for patients to consider whether
they want the contralateral breast removed for
prophylaxis.
Core biopsy is the optimal method for diagnosing LABC because this provides adequate
tissue for immunohistochemistry (IHC) staining for estrogen receptor (ER), progesterone
receptor (PR), and human epidermal growth
factor receptor 2 (Her-2/neu), which are imperative to make decisions regarding systemic
therapy, which will be the first step. Multiple
cores should be taken to confirm the entire
mass is invasive because occasionally (although
rarely), ductal carcinoma in situ (DCIS) can
present as a large bulky mass. If the core biopsy
is non-diagnostic, negative, or suggests primarily noninvasive disease, the surgeon should
perform an incisional biopsy of the breast for
a more definitive diagnosis. If patients have
skin involvement, a punch biopsy of the
affected skin can also provide the diagnosis.
Because of the high risk of distant disease, all
patients with LABC should undergo a thorough
search for metastatic disease. The incidence of
metastatic disease rises from approximately
2% to 3% for early stage disease to as high as
Treatment of Locally Advanced Breast Cancer
History of Treatment for Locally Advanced Breast Cancer
Because breast cancer had always been a surgical disease, surgery was also the primary therapy
for LABC, specifically the radical mastectomy.
Haagensen and Stout first reported the extremely poor outcomes associated with this
approach, with high local recurrence rates and
poor survival. It was this experience on which
early staging systems for breast cancer were
based, identifying poor candidates for surgery
as those with extensive breast skin edema, satellitosis, intercostal/parasternal nodules, lymphedema of the arm, supraclavicular metastases,
or IBC. Patients with ulceration, limited skin
edema, fixation, or bulky adenopathy were
not necessarily considered inoperable, but as
having a poor prognosis.
Given the limitations of surgery in
controlling LABC, the potential of radiation
was examined, but likewise yielded poor local
control and had minimal impact on survival.
A combination of radiation and surgery failed
to improve disease control. It was not until
the introduction of preoperative chemotherapy that improvements in the outcome of
patients with LABC were realized. When first
proposed, surgeons were hesitant to deliver
chemotherapy before surgery, worried not
only about an increase in surgical complications but also a negative impact on survival
secondary to delaying the operation. However,
several series not only showed that the operative morbidity was not worse, but also showed
that it may actually improve tumor downstaging. And in contrast to concerns that preoperative treatment and deferral of surgery may
increase rates of unresectability, approximately
80% of patients will have at least 50%