During the last quarter of the 20th century, significant changes have occurred in our understanding of the biology and management of operable breast cancer. Results from well-designed, well-conducted clinical trials have convincingly demonstrated that the extent of surgical resection is not paramount for patient outcome. Furthermore, the administration of systemic therapy following surgery has been shown to significantly improve both disease-free and overall survival in such patients.
There has been a shift in emphasis away from surgery as the sole treatment for operable breast cancer, and the use of systemic therapy has been adopted as an integral part of treatment in the majority of cases. With these developments, the question soon arose as to whether variations in the timing of systemic therapy administration might further influence the outcome of patients with breast cancer. Several biologic and clinical observations contributed support for the notion of evaluating such variations in timing of systemic therapy.
In 1988, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-18) in patients with operable breast cancer to compare preoperative vs postoperative administration of adjuvant chemotherapy. Following diagnosis of breast cancer by fine-needle aspiration or tru-cut biopsy, patients were randomized to receive either surgery (lumpectomy and axillary node dissection or modified radical mastectomy), followed by four courses of doxorubicin(Drug information on doxorubicin)/cyclophosphamide (Cytoxan, Neosar) chemotherapy every 21 days, or the same chemotherapy first followed by surgery.
All patients 50 years of age or older were also given tamoxifen(Drug information on tamoxifen) (Nolvadex) 10 mg, twice daily, for 5 years, starting after the completion of adjuvant chemotherapy. Patients undergoing lumpectomy also received postoperative radiotherapy. Preoperative chemotherapy administration resulted in a high rate of clinical response (79%) and a low rate of complete pathologic tumor response (about 11%). In addition, there was evidence of axillary nodal downstaging and an increase in the rate of lumpectomy.[3,4]
The development of taxoids and the demonstration of their significant antitumor activity in patients with advanced breast cancer provide the rationale for investigating docetaxel(Drug information on docetaxel) in the neoadjuvant setting. In 1995, the NSABP implemented protocol B-27, a randomized trial designed to evaluate the safety and efficacy of docetaxel administered in the preoperative or the postoperative setting, following preoperative doxorubicin/cyclophosphamide chemotherapy.
The primary objective of the study is to determine whether the addition of four courses of preoperative or postoperative docetaxel, following four courses of preoperative doxorubicin/cyclophosphamide, can more effectively prolong disease-free and overall survival in patients with operable breast cancer than four courses of preoperative doxorubicin/cyclophosphamide alone.
Secondary objectives are to determine whether the additional preoperative docetaxel following preoperative doxorubicin/cyclophosphamide: (1) increases the rates of locoregional clinical response and pathologic complete response, (2) contributes to further pathologic nodal downstaging, and (3) increases the number of patients who receive lumpectomy.
Additional secondary objectives are to determine whether the addition of postoperative docetaxel following preoperative doxorubicin/cyclophosphamide increases disease-free and overall survival in specific subgroups of patients; ie, as defined by nodal status.
Following stratification according to age, clinical tumor size, and clinical nodal status, patients are randomized to receive one of three regimens: (1) four courses of preoperative doxorubicin/cyclophosphamide chemotherapy followed by surgery (group 1); (2) four courses of preoperative doxorubicin/cyclophosphamide, followed by four courses of preoperative docetaxel, followed by surgery (group 2); or (3) four courses of preoperative doxorubicin/cyclophosphamide, followed by surgery, followed by four courses of postoperative docetaxel (group 3). All patients receive tamoxifen daily beginning on day 1 of the first doxorubicin/cyclophosphamide course and continuing for 5 years (Figure 1).
The eligibility criteria for this study are as follows:
- Localized, operable carcinoma of the breast
- Diagnosis obtained by fine-needle aspiration or core biopsy
- Tumor palpable on physical examination (T1c-3, N0, M0 or T1-3, N1, M0)
- Tumor movable in relation to the muscle, chest wall, and overlying skin
- Nodes of any size, but movable in relation to the chest wall and neurovascular bundle
- No arm edema
Patients with no clinically palpable nodes are eligible only when the greatest diameter of the tumor exceeds 1 cm. Patients with clinically palpable nodes are eligible regardless of tumor size.
All three treatment groups receive four 21-day courses of 60 mg/m² of doxorubicin plus 600 mg/m² of cyclophosphamide(Drug information on cyclophosphamide) and oral tamoxifen, 10 mg, twice daily, beginning on day 1 of the first course for a planned 5-year treatment duration. The type of surgery is left to the discretion of the surgeon, but surgeons are asked to state prior to randomization their intended procedure if a patient was not to receive preoperative chemotherapy.
Patients who undergo a lumpectomy also receive postoperative breast irradiation. Patients in group 2 receive, in addition, four 21-day courses of 100 mg/m² of docetaxel given intravenously after four courses of the doxorubicin/cyclophosphamide regimen and before surgery. Patients in group 3 receive, in addition, four 21-day courses of 100 mg/m²of intravenous docetaxel after surgery.
All patients in groups 2 and 3 receive the following premedications during each docetaxel course: 20 mg of oral dexamethasone(Drug information on dexamethasone), 12 and 6 hours before treatment; 50 mg of diphenhydramine(Drug information on diphenhydramine) intravenously, 1 hour before treatment; and either 300 mg of cimetidine(Drug information on cimetidine) or 50 of mg ranitidine(Drug information on ranitidine) intravenously, also 1 hour before treatment.
Assessments of Tumor Response and Statistical Considerations
The criteria for assessing tumor response in this trial are those used in the previous NSABP protocol (B-18). Tumor measurements are taken after each cycle of chemotherapy and before surgery. Response is assessed when chemotherapy (preoperative doxorubicin/cyclophosphamide alone or followed by preoperative docetaxel) has been completed, prior to surgery.
This study is scheduled to accrue an average of 318 patients per year over 5 years, for a total of 1,606 patients. Survival and disease-free survival are the primary end points. With this number of patients, at 1.5 years of additional follow-up, a 33% improvement in disease-free survival can be detected, with a power of 0.81. After 3 years of additional follow-up, a 40% reduction in mortality can be detected, with a power of 0.80.
Patient Accrual and Patient Characteristics
The trial opened in December 1995. As of November 1996, approximately 11 months into the trial, 283 patients were entered. Patient and clinical characteristics at study entry for patients accrued to date are shown in Table 1. Slightly more than half the patients are younger than 50 years of age. Nearly half (47% to 48%) of the tumors are more than 4.0 cm in greatest diameter. Biopsy was performed by fine-needle aspiration in a little more than half of the patients. Slightly more than two-thirds of the patients had clinically negative nodes. Lumpectomy was the proposed surgery at entry for 40% to 43% of patients. The distribution of all these characteristics was similar across treatment groups.
The results for toxicity are preliminary: as of November 1996, toxicity information is available on 167 patients who received doxorubicin/cyclophosphamide preoperatively (all three groups combined), 29 patients who received docetaxel preoperatively, and 23 patients who received docetaxel postoperatively. So far there have been no unexpected toxicities, but the data are too preliminary to report in detail. Toxicity information is likely to change as more patients complete all of the courses of their assigned chemotherapy.
NSABP B-27 is designed to assess the effect of adding docetaxel to the neoadjuvant chemotherapy regimen of doxorubicin/cyclophosphamide. In the first 11 months of the study, 283 patients--of a projected 1,606 patients over a 5-year period--have been entered. Average accrual during the past 6 months has exceeded the projected average accrual. This preliminary report shows no unexpected toxicities. Thus far, the incorporation of docetaxel in the manner described with doxorubicin/cyclophosphamide in the neoadjuvant/adjuvant setting appears to be safe and feasible.
In contrast to the common practice of 5 days or less of premedication with docetaxel, this study mandates only 1 day of corticosteroids and antihistamines. The 1-day regimen usually recommended with paclitaxel(Drug information on paclitaxel) (Taxol) was chosen for this study because the number of courses of docetaxel in this protocol is limited to four. The development of clinically significant edema requiring treatment discontinuation is considered unlikely. For this reason, and because this study may serve as a model for subsequent adjuvant studies, a shorter course of steroid premedication is used.
In the absence of the recommended steroid premedication regimen, and assuming a maximum cumulative docetaxel dose of 400 mg/m², some degree of edema can be expected in about half of the patients. These patients are carefully monitored. Should edema become a problem during the course of the trial, the premedication regimen may be amended as necessary.
Advantages of Preoperative Chemotherapy
The role of preoperative chemotherapy in the treatment of operable breast cancer is currently evolving. Until data from randomized clinical trials demonstrate that preoperative chemotherapy results in disease-free and overall survival rates that are superior, or equivalent, to those achieved with postoperative chemotherapy, preoperative chemotherapy may be considered only in women with tumors too large for breast-conserving surgery.
There may be an additional advantage to preoperative chemotherapy over postoperative chemotherapy, even if these two treatments result in the same disease-free and overall survival rates. This advantage is provided that a correlation between clinical and/or pathologic response to chemotherapy and outcome, can be convincingly demonstrated. If this is the case, clinical and pathologic tumor response to preoperative chemotherapy can be used as a prognostic factor for outcome and as a guide for further locoregional and systemic therapy.
From a research standpoint, there is ample rationale for continuing to evaluate the role of preoperative chemotherapy in patients with operable breast cancer. If response to preoperative chemotherapy correlates with patient outcome, response to chemotherapy can then be used as an intermediate end point in testing new chemotherapeutic regimens or new drugs administered after well-established regimens.
This approach offers an additional clinical advantage with strong biologic implications. For example, it is conceivable that subgroups of patients with a high likelihood of pathologic complete tumor response could be identified through the evaluation of proven and putative prognostic tumor markers (eg, estrogen receptors, progesterone(Drug information on progesterone) receptors, ploidy and S-phase, erb-B2 and p53 oncogenes, and other tumor oncogenes and growth factors). The potential correlation of such markers, individually or in combination with tumor response to preoperative chemotherapy and outcome, could ultimately spare some patients from radiation or surgical resection.
Furthermore, serially monitoring tumor marker changes while a patient is undergoing preoperative chemotherapy may provide biologic insight into the nature and function of these tumor markers. Knowledge may also be obtained regarding the mechanisms of action of new chemotherapeutic agents or new treatment modalities.
Two ancillary trials to the B-27 protocol were recently implemented to study serum and tumor biomarkers as they relate to outcome and response to preoperative doxorubicin/cyclophosphamide or docetaxel chemotherapy. The first (NSABP Protocol B-27.1) is designed to evaluate the usefulness of serum erb-B2 extracellular domain and serum erb-B2 antibodies for predicting response to preoperative chemotherapy and long-term outcome. In addition, by obtaining serum at specified times (before administration and after completion of preoperative chemotherapy, after surgery, 1 year after randomization, and at the time of recurrence), the study will determine whether potential changes in the levels of erb-B2 extracellular domain and erb-B2 antibodies are induced by chemotherapy or are associated with breast cancer recurrence.
The second trial (NSABP Protocol B-27.2) is designed to evaluate the usefulness of tumor biomarkers obtained by fine-needle aspiration or core biopsy in predicting response to preoperative chemotherapy and long-term outcome in B-27 patients. The study will also assess whether preoperative chemotherapy results in changes in tumor biomarker expression, and whether these changes can be correlated with tumor response and long-term outcome.
Finally, if there is prolonged disease-free or overall survival with the addition of preoperative or postoperative docetaxel after preoperative doxorubicin/cyclophosphamide, the study will examine whether this prolongation is associated with the expression of certain biomarkers. The following biomarkers will be evaluated both in material obtained before preoperative chemotherapy and in material obtained at the time of surgery: nuclear grade, estrogen and progesterone receptors, proliferation markers, p53 oncogene mutations, erb-B2 overexpression, P-glycoprotein, and apoptosis markers (bcl-2).