The substantial antitumor activity of docetaxel (Taxotere) in first-
and second-line chemotherapy for patients with metastatic breast cancer
provides the rationale for further investigation of this agent in other
breast cancer treatment settings.[1-11] One area is the incorporation of
docetaxel into multimodality regimens in which chemotherapy and/or endocrine
therapy is combined with surgery and radiation.
Earlier studies have shown that induction chemotherapy may result in
significant reductions in the size of the primary tumor, thereby increasing
the number of candidates for breast conservation by a combination of surgery
and radiation.[12-16] One benefit of using neoadjuvant therapy in this
setting is that it allows clinical and pathological assessment of tumor
response to the chemotherapy regimen.[17,18]
In a randomized study by Powles and colleagues, use of neoadjuvant
chemoendocrine therapy and postsurgery chemotherapy in 212 women with primary
operable breast cancer was evaluated. Of these 212 patients, 105 were randomized
to receive neoadjuvant treatment and received 4 cycles of chemotherapy
for 3 months before surgery, followed by another 4 cycles after surgery.
For comparison, 107 patients were randomized to adjuvant therapy and received
8 cycles of chemotherapy over 6 months after surgery.
The findings from this trial showed that neoadjuvant therapy results
in an overall response rate of 85% and a complete response in 10% of patients.
In addition, there was a significant reduction in the requirement for mastectomy
in patients who received neoadjuvant treatment (13%) compared with those
who received adjuvant therapy (28%) (P < .005).
We conducted a phase II study to determine the clinical response rate
to primary therapy with docetaxel followed by surgery, cyclophosphamide
(Cytoxan, Neosar), and doxorubicin, and radiation with or without adjuvant
tamoxifen (Nolvadex) in patients with stage III breast cancer. This preliminary
analysis addresses the response rate, side effects, and toxicity profile
of this therapeutic approach.
Women aged 18 to 75 years with stage III breast cancer were accrued
into this open-label, phase II multicenter study. Patients with locally
advanced adenocarcinoma of the breast and measurable and/or evaluable disease
were eligible for entry into the study provided they had a performance
status of at least 60% (Karnofsky index) and had not received previous
Laboratory entry criteria included the following values: absolute neutrophil
count ³ 2.0 × 109/L; a platelet count ³ 100.0 × 109/L; total bilirubin £ 1.25 × upper
normal limit (UNL); aspartate aminotransferase (ASAT) or alanine aminotransferase
(ALAT) £ 3 × UNL; alkaline phosphatase £ 6 × UNL;
ASAT or ALAT or both £ 1.5 × UNL associated with alkaline phosphatase £
2.5 × UNL; serum creatinine £ 1.5 × UNL; a resting
left ventricular ejection fraction above the lower normal limit of the
institution, as measured by echocardiography or radionuclide angiocardiography.
Patients with locally advanced stage III breast cancer were initially
treated with 4 cycles of 100 mg/m² of docetaxel administered as a
1-hour intravenous infusion once every 3 weeks. Following the 4 cycles
of docetaxel, patients underwent either breast-conserving surgery or mastectomy.
Standard-dose doxorubicin/cyclophosphamide chemotherapy--4 cycles of 60
mg/m² of Adriamycin and 600 mg/m² of cyclophosphamide--was initiated
following surgery. Radiation therapy was then delivered, which varied according
to the type of surgery performed.
For patients who had undergone breast-conserving surgery, radiation
consisted of conventional fractionation at a dose of 5,000 or greater cGy
(180 to 200 cGy/day) and a boost to a total tumor dose of 6,040 cGy. For
patients who had undergone modified radical mastectomy, radiation therapy
to the chest wall and supraclavicular region was employed to a total dose
of 5,000 or greater cGy. Tamoxifen therapy (20 mg/day for 5 years) was
provided to all patients who were hormone-receptor positive or who were
over the age of 50 years.
All patients received premedication with 8 mg of oral dexamethasone
twice daily for 5 days, starting 1 day prior to docetaxel administration.
Growth factor support with granulocyte colony-stimulating factor (G-CSF)
(filgrastim [Neupogen]) was provided to patients who developed febrile
neutropenia (and was initiated prophylactically to these patients on subsequent
Tumor measurements were performed before initiation of therapy and every
two cycles thereafter, according to the World Health Organization criteria.
The primary efficacy variable was clinical response rate, defined as
the percentage of patients who achieved a complete or partial response.
In patients who received at least 2 cycles of therapy, response to treatment
was classified as follows: complete response, partial response, stable
disease, or progressive disease. A complete response was defined as the
complete resolution of all known lesions on 2 separate measurements at
least 4 weeks apart. A partial response was defined as reduction of tumor
volume by at least 50%. Stable disease was defined as a decrease of < 50% or an increase of < 25%. Progressive disease was defined
as a > 25% increase in an existing tumor or the appearance of
The secondary efficacy variable was time to progression, calculated
from the date of the administration of the first cycle of chemotherapy
to the first sign of disease progression.
This preliminary analysis is based on data from 33 patients. The demographics
are listed in Table 1. The mean age of
patients was 50 years (range, 27 to 68 years). Thirty-two of the 33 patients
had a Karnofsky performance status of 90%. A total of 12 patients (36%)
had stage IIIA disease and 16 (49%) had stage IIIB disease. The remaining
5 patients (15%) were unspecified stage III, but appeared to have large
primary tumors > 5 cm, with no clear indication of the nodal status
on clinical examination. A total of 120 cycles were administered during
Partial and complete responses were achieved in 22 (67%) and 6 (18%)
patients, respectively, for an overall response rate of 85% (Table
2). Disease was stable in 4 patients (12%) and progressed in 1(3%).
Of the 6 patients with complete clinical responses, 1 patient was actually
confirmed to have achieved a complete pathologic response at the time of
Data on the time-to-progression and disease-free survival after 1 and
2 years of treatment are not yet available.
The primary toxicity observed during the docetaxel administration portion
of this trial was myelosuppression (Table
3). Febrile neutropenia was noted in 8 patients (24%) and in 8 of the
120 treatment cycles (7%) administered. Grade 4 neutropenia was experienced
by 31 patients (94%) during at least 1 cycle. The majority of patients
(88%) experienced grade 4 neutropenia during the first cycle, with a median
duration of 7 days or less. Thrombocytopenia did not occur. Although anemia
did occur, no patient required a blood transfusion.
Nonhematologic toxicities are shown in Table
4. The most common National Cancer Institute (NCI) gradeable toxicities
included alopecia (97%), nausea (51%), diarrhea (46%), and stomatitis (35%).
Grade 3 nonhematologic toxicities were uncommon and included diarrhea (6%),
stomatitis (6%), allergy (3%), and nausea (3%). Grade 3 to 4 or severe
neurotoxicity was not observed in any patient. Other toxicities not graded
using the NCI criteria included asthenia, which was noted in 70% of patients,
but was severe in only 9%. Peripheral edema and nail disorders were mild
to moderate in severity, with no reports of severe cases.
The preliminary results from this phase II study suggest that single-agent
docetaxel has significant antitumor activity as neoadjuvant therapy in
patients with stage III breast cancer. The overall response rate was 85%,
with 18% complete responses. The most common toxicity was neutropenia;
however, only a small fraction of cases were associated with febrile neutropenia.
Future trials aimed at increasing the number of pathologic complete responses
in patients with stage III breast cancer may require the use of docetaxel
in combination with other active agents or the use of dose-dense scheduling
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