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The International Experience With Docetaxel in the Treatment of Breast Cancer

The International Experience With Docetaxel in the Treatment of Breast Cancer

ABSTRACT: The extensively studied agent docetaxel (Taxotere) has shown marked clinical activity in the treatment of anthracycline-resistant breast cancer. Phase I trials indicate that toxicities, such as mucositis and neutropenia, limit the administration of docetaxel to shorter perfusion schedules. Pharmacokinetic studies have shown that docetaxel's clearance by hepatic metabolism is correlated with a marked increase in risk of toxicity in patients with impaired liver function. Nevertheless, studies of docetaxel as front-line therapy for breast cancer were initiated because of its good activity against tumors in early studies and its close relationship to paclitaxel (Taxol), an agent with proven efficacy. Phase II studies have demonstrated excellent activity for docetaxel as a single agent, with an overall response rate of 61% in trials of a 100-mg/m² dose. A phase III study is currently comparing docetaxel with paclitaxel as single-agent therapy. Docetaxel is expected to provide a better response rate but a higher incidence of neutropenia. The agent shows promise in adjuvant therapy, with very high response rates in anthracycline-resistant patients. Preliminary results of tests using docetaxel in combination with doxorubicin show high objective response rates but low complete response rates; early results suggest that this combination may have some advantages over paclitaxel/doxorubicin. [ONCOLOGY 11(Suppl):38-42, 1997]


Introduction

Docetaxel (Taxotere) is the second taxoid to be widely evaluated in
clinical trials. It has some specific apparent advantages and disadvantages
relative to the first described taxoid, paclitaxel (Taxol). Docetaxel has
been approved for the treatment of anthracycline-resistant breast cancer;
in this setting, a series of trials shows it to have clinical activity
that is at least as good as and perhaps superior to any other single agent.

Paclitaxel was discovered serendipitously 34 years ago by a program
screening natural products. The recognition of abnormal stabilization of
microtubule assembly[1,2] as paclitaxel's mechanism of action allowed for
rapid laboratory screening of related compounds.[3] Docetaxel was discovered
during these screening programs, which were carried out in the early 1980s.

A semisynthetic product, docetaxel is derived from the European yew
(Taxus baccata). Although docetaxel and paclitaxel appear to bind
to the same site on microtubules, docetaxel seems to bind with higher affinity.[4]
In addition, in some cell culture systems, docetaxel accumulated to higher
intracellular concentrations and had slower efflux than did paclitaxel.[5]
This preclinical work suggested that docetaxel would be more potent than
paclitaxel but left open the question of whether it would have a more favorable
therapeutic index.

The next logical step in the development of docetaxel was evaluation
of the agent's activity against a variety of cell lines in culture. These
studies showed that docetaxel had activity against cell lines from a wide
variety of tumor types, including cell lines derived from breast, colon,
ovarian, sarcoma, and bladder cancers.[6-8] Studies using human primary
tumors showed docetaxel to have a broad range of activity and to be partially
non-cross-resistant with paclitaxel and doxorubicin.[9,10] Preclinical
evaluation has shown that overexpression of p-glycoprotein (the product
of the gene mdr-1) and tubulin alterations are two mechanisms of
resistance to docetaxel.

Docetaxel was also evaluated against a number of animal tumor models.
In these studies, docetaxel had a high level of activity against many but
not all mammary tumor models. The agent also had a high level of activity
in nude mice with human mammary tumor xenografts (MX-1).[11]

Phase I Trials

Docetaxel has been extensively evaluated in phase I trials. The major
dose- limiting toxicities observed in these trials were mucositis and neutropenia,
with mucositis more prominent in the extended regimens (Table
1
). For this reason, the schedule selected for phase II studies was
1 hour every 3 weeks, and neutropenia was expected to be the major dose-limiting
toxicity on this schedule.

Phase II studies of docetaxel with long perfusion times have not been
conducted because of the prominent mucositis that occurs with these schedules.
In the majority of phase II studies, docetaxel has been administered at
a dose of 100 mg/m² IV over 1 hour every 3 weeks.

Pharmacokinetics

Extensive studies of the pharmacokinetics of docetaxel have been conducted.[17]
The most important finding of these studies is the demonstration that docetaxel,
like paclitaxel, is cleared by hepatic metabolism. These studies have shown
a markedly lower clearance of docetaxel when there was concurrent elevation
of transaminases and alkaline phosphatase. The lower clearance rate of
docetaxel in these patients has been shown to correlate with a markedly
increased risk of toxicity (Table 2 and
Table 3). Docetaxel is also more toxic
in patients with elevated bilirubin levels,[18] and thus, is contraindicated
in patients with liver dysfunction.

The pharmacokinetic studies conducted in the phase I and II trials have
shown docetaxel to be largely protein bound. Values of maximum serum concentration
(Cmax) and area under the curve (AUC) values were proportional
to dose. Estimates of half-life (t½b) at the 100-mg/m²
dose ranged from 11.4 to 18.5 hours.

Phase
II Studies of Docetaxel in Breast Cancer Patients

Docetaxel was taken directly into front-line studies for the treatment
of breast cancer for several reasons. The drug had shown good activity
against mammary tumors in preclinical models, and a number of responses
in breast cancer patients had been seen in phase I trials. Also, paclitaxel,
a closely related agent, is known to have excellent activity in breast
cancer.

Several phase II trials have been conducted using docetaxel as front-line
therapy (Table 4). These trials found
excellent activity for docetaxel as a single agent, with an overall response
rate of 61% in the trials conducted with a dose of 100 mg/m².

Docetaxel
in Anthracycline-Resistant Breast Cancer

Currently, docetaxel is approved in the United States for the treatment
of anthracycline-resistant breast cancer. Approval of this indication was
based largely on the results of three trials (Table
5
). In all three trials, docetaxel was used to treat patients who had
anthracycline- or anthracenedione-resistant disease, defined as disease
progression during administration of one of these agents (as opposed to
simple prior exposure during adjuvant therapy). The European study (study
3) had the most rigorous definition of anthracycline resistance, allowing
only patients with intrinsic resistance and excluding those with acquired
resistance (ie, initial response to anthracyclines and then progression).

The overall response rate for patients in these studies was 41%. Table
6
shows that for patients with evaluable disease, the response rate
was well maintained in patients with visceral disease sites, such as the
liver, as well as in patients with multiple disease sites. These results
are quite striking, given the generally low response rates of other single
agents and combinations in such patients.

Docetaxel Toxicity

The major dose-limiting toxicity of docetaxel, given at 100 mg/m²
over 1 hour every 3 weeks, is neutropenia. Toxicity information for docetaxel
derived from phase II studies is summarized in Tables 2 and 3. It is clear
that for patients with hepatic compromise, docetaxel at a dose of 100 mg/m²,
has unacceptable toxicity. Even in patients with normal hepatic function,
docetaxel caused more than 90% of patients to develop grade 4 neutropenia,
but the neutropenia generally lasted less than 1 week, and only 4% of patients
per cycle developed neutropenia and fever. Other severe hematologic toxicities
are rare in patients with normal hepatic function.

Several types of nonhematologic toxicities were noted in these trials.
Acute hypersensitivity reactions and neurosensory reactions were rare.
Myalgias, when they occurred, were generally mild. Some patients experienced
severe skin reactions, with peeling of the skin particularly obvious on
the palms. Some patients developed severe asthenia, and a few developed
severe stomatitis.

A toxicity that at first seemed unique to docetaxel is a fluid retention
syndrome. This syndrome is the result of cumulative toxicity. It is gradual
in onset and reversible. In unpremedicated patients, the syndrome can become
severe, leading to treatment discontinuation.

The fluid retention syndrome seems to be ameliorated largely by the
present premedication regimen of dexamethasone, 8 mg bid orally, starting
the day of treatment and continuing for 5 consecutive days. Mild peripheral
edema may still occur on this regimen, but it can be easily managed with
oral diuretics.

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