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Neoadjuvant Chemotherapy for Operable Breast Cancer

Neoadjuvant Chemotherapy for Operable Breast Cancer

ABSTRACT: Adjuvant systemic chemotherapy has been shown to prolong survival in all subsets of patients with breast cancer. In addition, among patients with locally advanced breast cancer, neoadjuvant or preoperative chemotherapy has improved the ability to perform breast-conserving therapy. This observation, combined with multiple preclinical hypotheses and the results of laboratory studies, has prompted investigation of neoadjuvant chemotherapy as a treatment strategy for operable breast cancer. In this article, both the evidence supporting this treatment approach and some of the problems associated with it are reviewed. Currently, seven randomized studies comparing neoadjuvant chemotherapy followed by surgery or surgery followed, in turn, by adjuvant chemotherapy have been completed and their results analyzed. Despite exciting preclinical evidence, no trial to date has shown a survival advantage for the neoadjuvant treatment approach. Nonetheless, evidence from more recent phase III trials and the fact that neoadjuvant chemotherapy is not harmful to patients validate its use in operable breast cancer. [ONCOLOGY 16:871-898, 2002]

Compared with many other malignancies, operable breast
cancer (stages I-IIIA) has a long natural history with morbidity and mortality
caused primarily by local recurrence and distant metastases. Although local
therapy is essential for regional control, it does not completely address the
problem of future metastases. Even after aggressive surgery, women with axillary
lymph node involvement at the time of diagnosis have a poor prognosis without
additional therapy. In 1975, Fisher et al reported that only 25% of women with
lymph node involvement at the time of surgery were alive 10 years after
diagnosis.[1] In addition, 10% to 50% of patients with negative axillary lymph
nodes developed distant metastases following apparently curative surgery.

For many, this low survival rate was due to distant micrometastases already
present at the time of surgery. This realization led to a change in the
treatment paradigm in the second half of the 20th century, with the introduction
of systemic treatment modalities (chemotherapy and endocrine therapy) as
"adjuvants" to surgical therapy. Systemic adjuvant therapy of breast
cancer has improved survival in all subsets of patients with operable disease by
helping to eradicate micrometastases. This has been proven in multiple
randomized studies and confirmed in two recent meta-analyses—one evaluating
the benefit of tamoxifen[2] and the other evaluating systemic chemotherapy.[3]

Although effective, adjuvant systemic therapy of breast cancer cannot
completely eliminate the development of distant metastases. Thus, on the basis
of hypotheses generated from preclinical studies and from the use of presurgical
chemotherapy as treatment for locally advanced breast cancer, interest in using
the neoadjuvant approach to treat early-stage breast cancer has grown.

In animal models, removal of the primary tumor increases proliferation of
cancer cells at sites of metastases.[4] It has, therefore, been hypothesized
that administering systemic chemotherapy prior to tumor removal helps minimize
micrometastases and prevent cancer growth that might otherwise occur after
removal of the primary tumor. In fact, one study found that when
cyclophosphamide (Cytoxan, Neosar) was administered to mice with implanted
mammary adenocarcinomas before removal of their largest tumors, it abrogated the
growth spurt of the remaining tumor deposits and provided optimal tumor
control.[5]

Tamoxifen administered in the preoperative setting had similar effects.
Administration of systemic chemotherapy to patients with intact primary tumors
might, therefore, help decrease systemic micrometastases and improve overall
survival. It has also been hypothesized that preoperative systemic treatment
reaches tumors earlier than does postoperative adjuvant therapy, therefore
confronting fewer micrometastases.[6] Preoperative systemic therapy would also
reach the primary tumor site before any surgical destruction of vascular access
to the tumor-bearing area occurs.

Beyond the benefits observed in research studies evaluating tumors in vitro
and in vivo, the benefits of neoadjuvant chemotherapy have been seen in its use
as a treatment strategy for locally advanced breast cancer. Induction
(neoadjuvant) therapy of locally advanced breast cancer produces an objective
response in 60% to 80% of patients, with approximately 10% to 20% achieving a
clinical complete response (CR).[7] Many tumors initially considered inoperable
can be rendered operable by neoadjuvant chemotherapy or endocrine therapy, and
this ability to downstage multiple patients with large tumors could also
theoretically translate into improved rates of breast conservation for patients
with earlier-stage disease. Some researchers have proposed this approach as a
method of testing the in vivo response of cancer to a particular systemic
treatment regimen.[8]

Early Studies—Promise and Problems

Most studies of preoperative systemic therapy have been conducted using
chemotherapy, although the results of a few studies of neoadjuvant endocrine
therapy are available.[9] Initial nonrandomized studies evaluating the benefit
of neoadjuvant chemotherapy in operable breast cancer began in the early 1980s
and, over the next 2 decades, confirmed that this approach was feasible for
early breast cancer (Table 1).[9-17] These studies were highly heterogeneous in
many aspects and, thus, cannot be directly compared to determine the overall
efficacy of any one treatment approach. While highlighting the potential of
neoadjuvant chemotherapy in the treatment of early-stage breast cancer, these
studies (and others) have illustrated many of the difficulties associated with
evaluation of the benefits of neoadjuvant chemotherapy.

Predicting Response to Therapy

One theoretical benefit of neoadjuvant chemotherapy is that it provides the
ability to evaluate the in vivo response of disease to a specific regimen. This
is potentially useful, given that there are no reliable methods of predicting
response to postoperative adjuvant chemotherapy—a procedure that is,
therefore, given "blindly." Although multiple attempts have been made
to predict response to chemotherapy on the basis of the baseline characteristics
of the primary tumor (grade, hormone-receptor status, S-phase fraction, and HER2
or p53 status), no method has proven reliable. Response to therapy, especially
pathologic CR, has been reproducibly associated with long-term survival.

During neoadjuvant treatment, a major reduction (> 50%) in tumor
dimensions predicts better outcome and encourages continuation of treatment with
the same regimen. Conversely, if little apparent benefit is being achieved with
a particular treatment, that treatment can be stopped to avoid further risk of
side effects and toxicity, and the regimen can be changed to an alternative drug
or combination that may produce a superior response. As shown in Table
1
, high
overall response rates were associated with the various regimens used in
clinical trials, despite the very heterogeneous groups of patients included in
these studies.

Breast-Conserving Therapy

High response rates may allow more patients to be eligible for
breast-conserving therapy. In the early studies presented in Table
1
, the
criteria used to determine eligibility for breast-conserving therapy were not
uniform, and, therefore, a comparison of this end point between trials is not
possible. Moreover, the results were not compared with those of a control arm of
surgery followed by adjuvant chemotherapy. The rates of breast-conserving
therapy in these studies varied widely, ranging from 7% to 88%. However, these
rates may be misleading, because the criteria used to determine operability were
not uniform between trials.

The study by Schwartz et al was apparently initiated in 1979. However,
breast-conserving therapy was not routinely used until 1983.[10] Among patients
receiving neoadjuvant chemotherapy after 1990, the percentage who undergo
breast-conserving therapy has increased to 75% of those evaluated. In some
studies, an initial tumor size > 3 cm precluded patients from
breast-conserving therapy[11,12]; in others, this approach was offered more
liberally, depending only on the ratio of tumor size to breast size.[18] The
studies using the first, more restrictive, criteria would likely be more
successful in extending the indications for breast-conserving therapy after
preoperative chemotherapy than would the studies using a more liberal set of
criteria. Overall, these studies illustrate that breast-conserving therapy can
be offered to a large percentage of patients who receive neoadjuvant therapy.

Clinical Response and Long-Term Outcome

The response of an individual tumor to treatment could be used as a primary
end point to predict long-term outcome. Clinical response has been correlated
with survival in trials evaluating neoadjuvant chemotherapy. In the study by
Schwartz et al, patients whose tumor responses were amenable to
breast-conserving therapy survived longer than did patients with similarly
staged disease who were receiving chemotherapy and ultimately required
mastectomy, although the differences were not significant.[10] Similar findings
were described by Bonadonna et al.[11,12]

Other reviews, by McCready et al and Kuerer et al, found that clinical
response to neoadjuvant chemotherapy is a strong predictor of disease-free
survival (P = .046).[19,20] In the second study,[20] patients who
achieved a clinical CR had a 3-year disease-free survival rate of 95%, whereas
patients with a clinical partial response (PR) or minor response had a 3-year
disease-free survival rate of only 66%.

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