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
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/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 (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 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
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,
- Tumor movable in relation to the muscle, chest wall, and overlying
- Nodes of any size, but movable in relation to the chest wall and neurovascular
- 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 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, 12 and 6 hours
before treatment; 50 mg of diphenhydramine intravenously, 1 hour before
treatment; and either 300 mg of cimetidine or 50 of mg 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 (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 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
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
1. Early Breast Cancer Trialists' Collaborative Group: Effects of radiotherapy
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N Engl J Med 333:1444-1455,1995.
2. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment
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trials involving 31,000 recurrences and 24,000 deaths among 75,000 women.
Lancet. 339:1-15, 71-85, 1992.
3. Fisher B, Rockette H, Robidoux A, et al: Effect of preoperative therapy
for breast cancer (BC) on local-regional disease: First report of NSABP
B-18 (abstract 57). Proc Am Soc Clin Oncol 13:64, 1994.
4. Mamounas E, Fisher B, Rockette H, et al: Clinical and pathologic
local-regional response of operable breast cancer (BC) to preoperative
chemotherapy: Results from NSABP B-18 (abstract). Society of Surgical Oncology
Meeting; Atlanta, GA, March 20-24, 1996.
5. Data on file. Rhone-Poulenc Rorer Pharmaceuticals, Inc. Collegeville,
6. Bristol-Myers Squibb Oncology. Taxol (paclitaxel) for injection concentrate
prescribing information, in Physicians' Desk Reference, 50th ed, pp 714-717.
Montvale, New Jersey, Medical Economics, 1996.
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