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EDITORIALS |
From the Department of Surgery, University of Wisconsin, Madison, Wisconsin.
Correspondence: Address correspondence to: Tara M. Breslin, MD, Department of Surgery, University of Wisconsin, 600 Highland Ave., H4/744 CSC, Madison, WI 53792; Fax: 608-263-7652; E-mail: Breslin{at}surgery.wisc.edu
In the July issue of the Annals of Surgical Oncology, Danforth et al.1 reported results from a prospective randomized trial evaluating preoperative versus postoperative chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, and cyclophosphamide/granulocyte-colony-stimulating factor for stage II breast cancer. Study end points included objective clinical response to preoperative chemotherapy, pathologic complete response, incidence and number of axillary metastases, breast conservation rate, and overall and disease-free survival. This study, which opened in 1990, closed early due to slow accrual, and results from 53 (130 subject accrual target) randomized subjects were reported. At 9 years of median potential follow-up, 76.5% had evidence of complete or partial clinical response in the breast tumor or palpable axillary nodes, and two patients had a complete pathologic response. The incidence and number of axillary metastases was lower in the preoperative chemotherapy group. There was no difference in overall or disease-free survival between the preoperative and postoperative chemotherapy arms, and breast conservation rates were similar in the two groups. The authors concluded that the preoperative regimen was effective against local/regional tumor in stage II breast cancer but was otherwise comparable with postoperative chemotherapy. The reported results are in agreement with other randomized prospective trials examining preoperative chemotherapy particularly the National Surgical Adjuvant Breast and Bowel Project B-18.2
With the information that preoperative chemotherapy does not improve on the survival benefits of postoperative chemotherapy, the authors explore the role for preoperative chemotherapy in early (stage I, II) breast cancer. Preoperative chemotherapy has been cited to offer several potential advantages including: (1) the ability to monitor treatment efficacy in vivo with the opportunity to discontinue ineffective therapy and change regimens based on response and (2) the potential for clinical downstaging thereby permitting breast-conserving surgery for patients with large operable tumors.
There are several platforms from which we can explore chemotherapeutic agents in the preoperative setting. The traditional end points of clinical and pathological downstaging mentioned above can be used to study novel agents or combinations of agents in the preoperative setting. In this case, the surgical management is delayed (usually several months) until either a complete course of therapy has been administered or clinical response has reached a plateau. Alternately, preoperative therapy could be administered for a short time (e.g., 1–3 weeks) after diagnosis without delay in the planned surgical procedure. In this setting, efficacy would be determined not by the traditional oncological end points of survival, tumor shrinkage, histological effect, and breast conservation rate but could instead be measured using surrogate markers of response and treatment effect. Dowsett described this nontherapeutic approach to preoperative therapy in a review published in Clinical Cancer Research.3 In most cases, study of biological characteristics of responsive and resistant tumors involves serial collection of tumor samples but could also as easily involve imaging technologies. Stearns and colleagues reported results from a pilot study in which serial core biopsies were collected in a cohort of women enrolled in a preoperative chemotherapy trial. In this trial, core biopsies were obtained before chemotherapy and at various time points during treatment to serially evaluate the tumors for apoptosis as well as a number of immunohistochemical markers. This study demonstrated that the study of surrogate biological end points using multiple core biopsies was feasible and yielded useful data about chemotherapy response.4 Several studies have looked at imaging surrogates for clinical response to cytotoxic chemotherapy, and magnetic resonance imaging demonstrates distinct imaging characteristics that are predictive of response.5 Positron emission tomography has also been studied and can differentiate responders from nonresponders early during a course of therapy.6 In summary, biologic and imaging assessments of response to agents administered for short periods in the preoperative period may provide a means for more rapidly screening of new agents and compounds for the treatment of breast cancer. In this way, it may become possible to rapidly identify responders and continue therapy while changing regimens for nonresponders.
Received for publication May 30, 2003. Accepted for publication June 4, 2003.
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