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Neoadjuvant Chemotherapy for Operable Breast Cancer

Neoadjuvant Chemotherapy for Operable Breast Cancer

Preoperative therapy delivers treatment at the earliest
time in a tumor’s natural history. Is it beneficial or harmful? Should it be
undertaken? The article by Drs. Green and Hortobagyi brings most aspects of
neoadjuvant therapy under one umbrella and poses several key questions.

Clinical investigation of neoadjuvant therapy for early breast cancer began
in the late 1970s,[1-3] at a time when postoperative adjuvant systemic therapy
was in its infancy, with only preliminary evidence supporting the use of the CMF
regimen (cyclophosphamide [Cytoxan, Neosar], methotrexate, fluorouracil). During
this time, doxorubicin was in development, but considered too toxic for routine
adjuvant therapy, taxanes had not been discovered, and trastuzumab (Herceptin)
was but a dream. Tamoxifen was gaining acceptance as an alternative to surgical
adrenalectomy, hypophysectomy, and estrogen therapy for stage IV breast cancer.
Breast cancer management was dominated by surgical and radiation approaches, and
medical oncology was an emerging specialty seeking to establish the role of
systemic adjuvant therapies.

Specific concerns surrounding the use of neoadjuvant chemotherapy included
fears of impaired wound healing, insecurities about survival benefits, and
medicolegal considerations concerning potential unexpected consequences.
Significant hurdles have since been overcome, and it is gratifying that the
neoadjuvant strategy is now accepted for routine management and research of many
oncologic conditions.

Neoadjuvant Therapy in the Late 1970s

One of the original rationales articulated in the late 1970s was the
hypothesis that neoadjuvant chemotherapy might reduce the risk of tumor
dissemination during noncurative surgical cytoreduction.[3] The putative
mechanism was thought to involve the release of growth factors triggered by
surgery, which would increase the tumor growth fraction and possibly lead to
invasiveness.[4,5] By disabling the tumor genome and its replication mechanisms,
neoadjuvant chemotherapy could theoretically be advantageous at times of
surgical stress.[6]

Other expected benefits included downstaging of large inoperable tumors,
while simultaneously treating systemic micrometastases. Thus, inoperable tumors
would become operable and a larger proportion of patients would be eligible for
breast-conserving therapy.[2,7] Furthermore, in vivo assessment of the
pathologic complete response (CR) rate would provide the best model for
predicting chemotherapy response or resistance.

The other less commonly discussed rationale involved the possibility of
averting the development of chemotherapy resistance.[6-8] This theory was based
on the Goldie and Coldman model,[9] predicting that the earliest possible
exposure to chemotherapy could reduce the chance of multidrug-resistance—a
desirable goal for chemotherapy treatment in general.[8] These events were
debated intensely at a dedicated cancer biology symposium,[10] and constitute
the basis for many ongoing research activities.

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