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The Current Status of Docetaxel for Metastatic Breast Cancer

The Current Status of Docetaxel for Metastatic Breast Cancer

ABSTRACT: Docetaxel (Taxotere) has been intensively investigated for the treatment of metastatic breast cancer, where it has proved to be one of the most active agents. Initial phase II studies in anthracycline-resistant metastatic breast cancer demonstrated impressive response rates that have been confirmed in phase III randomized trials. Docetaxel remains the only single agent to demonstrate a survival benefit in anthracycline-resistant patients. More recently, the combination of docetaxel with capecitabine (Xeloda) has demonstrated additional improvement in survival over docetaxel alone in a randomized phase III trial. In patients previously treated with an alkylating agent, docetaxel is the only single drug to demonstrate improved efficacy over doxorubicin in a randomized trial. Docetaxel has been investigated in combination with the anthracyclines doxorubicin and epirubicin in randomized trials. The docetaxel-containing regimens have consistently demonstrated improvement over the non-docetaxel-containing regimens. The efficacy and safety of weekly docetaxel has extended the line of investigation for combinations with agents normally administered on a weekly basis, such as vinorelbine [Navelbine], gemcitabine [Gemzar], and trastuzumab [Herceptin], with promising findings. In addition, the results of the triple-drug combination of docetaxel, a platinum salt (cisplatin or carboplatin), and trastuzumab have resulted in impressive response rates and time to progression in a population of metastatic breast cancer patients with HER2/neu-positive tumors. The consistent demonstration of a high level of efficacy with manageable toxicity ensures the continued widespread investigation of docetaxel in metastatic breast cancer. [ONCOLOGY 16(Suppl 6):17-26, 2002]

Breast cancer is the most common malignancy diagnosed
in women in industrialized countries. In the United States, an estimated 203,500
women will develop breast cancer in 2002 and 39,600 women are expected to die
from the disease the same year.[1] Effective chemotherapy prolongs survival and
provides important palliation for patients with metastatic breast cancer.
Historically, anthracycline-based regimens were considered superior to non-anthracycline-containing
regimens. The development of the taxanes in the 1990s opened new avenues for the
treatment of patients with metastatic breast cancer.

Docetaxel (Taxotere) is among the most active agents for metastatic breast
cancer. Initial phase II studies of docetaxel administered at 100 mg/m² showed
response rates of 53% to 68% in patients previously treated with
chemotherapy.[2-6] A multicenter phase II study of docetaxel at 75 mg/m² showed
a response rate of 52%.[7] Docetaxel is particularly active in patients with
anthracycline-resistant breast cancer. In two studies published simultaneously,
the objective response rates to docetaxel at 100 mg/m² in patients with breast
cancer resistant to anthracyclines were 53% and 57%, respectively.[2,3] Ando et
al[8] reported that docetaxel given at a dose of 60 mg/m² produces a response
rate of 49% in patients previously exposed to anthracyclines. The high response
rates observed with docetaxel in this patient population were confirmed in
randomized phase III trials.

Docetaxel in Anthracycline-Resistant Breast Cancer

In one study, docetaxel at 100 mg/m² was compared with mitomycin (Mutamycin)
plus vinblastine in patients with anthracycline-resistant metastatic breast
cancer.[9] Patients treated with docetaxel had significantly better response
rates (30% vs 11.6%, P < .0001), time to progression (19 vs 11 weeks, P =
.01) ), and overall survival (11.4 vs 8.7 months, P = .01). Another sudy
compared docetaxel at 100 mg/m² with sequential methotrexate at 200 mg/m² and
fluorouracil (5-FU) at 600mg/m², on days 1, 8, administered to patients with
advanced anthracycline-resistant breast cancer.[10] The results from this phase
III trial indicate that docetaxel is more active than the sequential two-drug
combination. Response rates (42% vs 21%, P < .001) and median time to
progression (6.3 months vs 3 months, P < .001) were significantly better in
the docetaxel arm in comparison with methotrexate/5-FU.

Another phase III study showed a higher response rate for docetaxel compared
with 5-FU plus vinorelbine (Navelbine) as second-line therapy.[11] Taken
together, these studies demonstrate that docetaxel is effective therapy against
anthracycline-resistant breast cancer, and, to date, docetaxel is the first and
only chemotherapeutic drug to demonstrate a survival benefit in this patient
population.

Historically, regimens that contained doxorubicin or epirubicin (Ellence)
were considered the first-line treatment of choice for patients with metastatic
breast cancer. This paradigm is being challenged by novel nonanthracycline
regimens. A randomized trial compared docetaxel at 100mg/m² with doxorubicin at
75 mg/m² in patients with metastatic breast cancer who had failed an
alkylating-containing regimen.[12] Docetaxel demonstrated significantly better
response rates compared with doxorubicin in this patient population (48% vs 33%,

P
= .008), with a trend toward improved time to progression. Of the 326
evaluable patients, 49% were classified as having resistant disease (progression
on prior chemotherapy), 70% of patients received docetaxel or doxorubicin as
second-line therapy for metastatic breast cancer, and 30% received this regimen
as first-line therapy for metastatic disease after having relapsed for 12
months or more after adjuvant therapy. These phase III results are the only time that a
single agent (ie, docetaxel) has outperformed the previous standard drug
(doxorubicin).[13,14]

The dose-limiting toxicity of docetaxel administered on an every 3-week
schedule is neutropenia. Other reported toxicities include skin reactions, nail
changes, neurosensory toxicity, and hypersensitivity reactions. Fluid retention
was a major concern in the initial phase I and II clinical trials of docetaxel,
in which patients had not received any premedication. A randomized study
conducted by the European Organization for Research and Treatment of Cancer
(EORTC) showed that the docetaxel-induced fluid retention could be reduced using
a premedication regimen of corticosteroids.[15]

Currently, docetaxel is approved by the Food and Drug Administration (FDA)
for the treatment of patients with locally advanced or metastatic breast cancer
after failure of prior chemotherapy. The approved outpatient regimen is 60 to
100 mg/m², administered intravenously for 1 hour every 3 weeks.[16] All patients
should be premedicated with oral corticosteroids, such as dexamethasone 16 mg/d
(eg, 8 mg bid), for 3 days starting 1 day prior to administration of docetaxel
in order to reduce the incidence and severity of fluid retention, as well as the
severity of hypersensitivity reactions. Of interest, a randomized clinical trial
exploring the efficacy of three doses of docetaxel (60 mg/m², 75 mg/m², and 100
mg/m²) has been closed to accrual. The results of this study will provide
additional details on the safety and efficacy of docetaxel in various doses.

Weekly Docetaxel

Docetaxel can be administered safely and effectively at lower doses when
given on a weekly schedule. Additionally, weekly docetaxel administration allows
for the possibility of combined use with alternative agents, including those
normally administered on a weekly basis (eg, trastuzumab [Herceptin],
vinorelbine), or those that become feasible in combination because of the change
in the hematologic toxicity profile of docetaxel.

In a phase II trial conducted by Loeffler et al, docetaxel 40 mg/m² was
administered once a week for 6 weeks, followed by a 2-week rest.[17] An overall
response rate of 47% was reported in 41 metastatic breast cancer patients who
had been previously exposed to chemotherapy, including prior paclitaxel. In this
study, no cases of grade 2 or greater neutropenia were seen with doses of less
than 43 mg/m² per week and grade 2 or higher thrombocytopenia was not observed.
In addition to causing minimal hematologic toxicity, the data showed that weekly
docetaxel was likely to be associated with a very low incidence of other acute
toxicities.

Another phase II study by Burstein et al, showed a response rate of 41% in a
population of 29 metastatic breast cancer patients treated with weekly
docetaxel, 40 mg/m² IV administered over 1 hour.[18] Treatment was administered
weekly for 6 weeks, followed by a 2-week rest. Hematological toxicity in this
study was minimal. Grade 3 neutropenia occurred in 14% of patients, and grade 4
neutropenia in none. There were no cases of grade 3 or 4 anemia or
thrombocytopenia of any grade. The incidence of nonhematologic toxicity was low,
in particular the rate of grade 3/4 neurologic toxicity was very low, with 3% of
patients experiencing neuropathy. Fatigue and asthenia occur with prolonged
therapy—as may fluid retention—although at a higher cumulative dose than is
seen with every-3-week schedules. A newly reported toxicity of frequent tearing
and visual problems, which is generally mild and manageable, may also occur
after substantial total exposure to weekly docetaxel, but was not reported at
the grade 3/4 level in this trial.

Hainsworth and colleagues reported on the use of docetaxel at 36 mg/m² per
week for 6 consecutive weeks, followed by 2 weeks without treatment.[19] A total
of 41 women with advanced breast cancer who were elderly (65 years or older) or who
were considered poor candidates for combination chemotherapy were enrolled on
the study. When assessed after 8 weeks of treatment, 12 of 36 assessable
patients had an objective response. An additional 14 patients had either a minor
response or stable disease and continued treatment with weekly docetaxel. One of
these patients subsequently achieved a partial response. Therefore, an overall
response rate of 36% was achieved with 72% of patients achieving either a
partial response or stable disease. Therapy was well tolerated, with infrequent
grade 3/4 leukopenia (4%). Nonhematologic toxicities included grade 3/4 fatigue
and asthenia (20%), which was difficult to distinguish as treatment- or
cancer-related.

A large study of weekly docetaxel for the treatment of first- and second-line
metastatic breast cancer patients is being conducted by Stemmler et al in
Germany.[20] In the first cycle, patients receive 35 mg/m² per week for 6
consecutive weeks and 2 weeks of rest, followed by treatment for 3 consecutive
weeks and 2 weeks of rest. Preliminary results in 33 evaluable patients
demonstrate an overall response rate of 36%, with stable disease in an
additional 40%. Toxicity data for 40 patients included grade 3 neutropenia (3%),
fluid retention (5%), nail toxicity (5%), and lacrimation (5%).

Comandone and colleagues treated 40 heavily pretreated metastatic breast
cancer patients, all of whom had received prior anthracyclines, with weekly
docetaxel.[21] Treatment consisted of three cycles of docetaxel at 40 mg/m² for
6 weeks, with 1 week of rest (one cycle). An overall response rate of 19% was
reported after two cycles of therapy with stable disease in 47.5% of patients.
Toxicity data after one cycle included grade 3 neutropenia (2.5%) and grade 3
fatigue (2.5%).

The University of Texas M. D. Anderson Cancer Center is conducting a phase
III study comparing weekly and every-3-week docetaxel in patients with
metastatic breast cancer. In this study, patients are randomized to docetaxel at
100 mg/m² every 3 weeks or docetaxel at 35 mg/m² per week for 6 weeks, followed
by 2 weeks of rest.

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