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(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil)). During this time, doxorubicin(Drug information on doxorubicin) was in development, but considered too toxic for routine adjuvant therapy, taxanes had not been discovered, and trastuzumab(Drug information on trastuzumab) (Herceptin) was but a dream. Tamoxifen(Drug information on 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. 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.
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, predicting that the earliest possible exposure to chemotherapy could reduce the chance of multidrug-resistancea desirable goal for chemotherapy treatment in general. These events were debated intensely at a dedicated cancer biology symposium, and constitute the basis for many ongoing research activities.