Clinical development of the taxoids began in 1983, when paclitaxel (Taxol)
was first used in cancer patients, but progressed slowly until the 1990s.
Docetaxel (Taxotere) first entered clinical trials in 1990, with phase
II studies beginning internationally in 1992. Increasing in vitro, in
vivo, and clinical experience indicate that the two taxoids, although related,
are different and should not be considered interchangeable.
In Vitro Studies
The cellular distributions of the taxoids differ in vitro for the same
extracellular concentration. At equilibrium, docetaxel achieves an intracellular
concentration triple that of paclitaxel, with one-third the rate of cellular
efflux (Figure 1). The resulting longer
cell residence time and higher intracellular accumulation may account for
its greater in vitro cytotoxicity. As shown in Figure
2, docetaxel is a highly potent inhibitor of cell replication in in
vitro murine and human models.
In vivo comparative data also suggest a higher degree of antitumor activity
for docetaxel. In the rapidly growing murine B16 melanoma model, known
to be sensitive to the taxoids, the increase in tumor burden, following
subcutaneous implantation of tumor cells in mice, was delayed after treatment
with docetaxel when compared with treatment with paclitaxel or control
Clinical Studies of Docetaxel as Monotherapy
Docetaxel has demonstrated high activity as a single agent in first-line
therapy for metastatic breast cancer, as shown in Table
1. Its efficacy is comparable with or higher than that of paclitaxel,
doxorubicin and other anthracyclines, and vinorelbine (Navelbine).[4-6]
Docetaxel is also highly effective in anthracycline-resistant disease.
The historical data are complicated by changes in the definition of resistance
over the past two decades. However, five recent trials demonstrate that
the taxoids, and docetaxel in particular, are more active than other, older
agents (Table 2).[5,6,15-21]
Requirements for Combination Chemotherapy
- Criteria for using a drug in concurrent combination chemotherapy include
- High activity against the disease
- Different mechanism of action from other agents in the combination
- No cross-resistance
- No overlapping toxicity
- Capacity to enhance the activity of other components of therapy
- Doses as near as possible to the full dose
Docetaxel demonstrates activity against breast cancer as high as or
higher than that of many commonly used agents, and toxicity is manageable.
Preclinical studies have demonstrated its unique mechanism of action: Docetaxel
enhances formation of microtubules and stabilizes the polymerization process.
No other agent attacks tumors in this way except paclitaxel, which has
small but important differences in its specific mechanism of action. Except
for paclitaxel, no cross-resistance has been found to any other antineoplastic
agent used in breast cancer treatment, and the cross-resistance between
docetaxel and paclitaxel is incomplete.
Docetaxel combinations were shown to be highly active in preclinical
models. Synergies, or at least additive effects, were observed in studies
with two- and even three-drug combinations, including docetaxel, cyclophosphamide
(Cytoxan, Neosar), fluorouracil (5-FU), vinorelbine, methotrexate, and
Some of the clinical trials have combined drugs at near their individual
maximum tolerated doses with relatively little increase in overall toxicity.
Docetaxel has been combined with the Vinca alkaloids, vincristine, vinblastine,
and vinorelbine (at 80% to 100% of the optimal dose), or with doxorubicin,
etoposide, cyclophosphamide, 5-FU, and methotrexate (at 60% to 70% of the
The mechanisms of resistance to the taxoids are not completely understood,
although the mdr gene, abnormal tubulin, and perhaps other factors
may be responsible. Cell lines resistant to 5-FU, vincristine, cisplatin
(Platinol), etoposide, or paclitaxel are not necessarily cross-resistant
Some mechanisms of resistance to docetaxel and anthracyclines are shared,
eg, increased drug efflux and defective apoptotic mechanisms. Others
differ, eg, increased topoisomerases and altered tubulin structure.
As shown in Table 2, docetaxel exhibits
high activity in anthracycline-resistant metastatic breast cancer, suggesting
partial cross-resistance between docetaxel and the anthracyclines.
Anthracycline Combinations in First-Line Therapy
A phase I trial, reported more fully in this supplement by Diéras
et al, defined the maximum tolerated doses in women with advanced or metastatic
breast cancer as 50 mg/m² of doxorubicin, followed by 85 mg/m²
of docetaxel. The dose-limiting toxicity was febrile neutropenia. Side
effects were tolerable, with no reported congestive heart failure. Responses
were observed at all dose levels, with response rates as high as 90% at
the recommended dose levels, 50 mg/m² of doxorubicin followed by 75
mg/m² of docetaxel.
A phase III study of first-line therapy has been initiated to compare
50 mg/m² of doxorubicin plus 75 mg/m² of docetaxel, with 60 mg/m²
of doxorubicin plus 600 mg/m² of cyclophosphamide, a standard regimen
in metastatic and primary breast cancer.
In another phase III trial, 75 mg/m² of docetaxel will be compared
with 500 mg/m² of 5-FU, each in combination with 50 mg/m² of
doxorubicin and 500 mg/m² of cyclophosphamide. Nabholtz et al describe
preliminary results of a pilot feasibility study for the docetaxel arm
of this trial in this supplement.
The scheduling of docetaxel/doxorubicin combination therapy will be
explored in a three-arm trial. The first group of patients will receive
60 mg/m² of docetaxel plus 60 mg/m² of doxorubicin. The second
group will receive 100 mg/m² of docetaxel followed by 75 mg/m²
of doxorubicin in a sequential schedule. The third group will receive the
two agents at the same doses as the second group, but in an alternating
There are also trials in development that do not involve anthracyclines.
In one trial, 85 mg/m² of docetaxel will be combined with 20 mg/m²
of vinorelbine on days 1 and 5 of the course of therapy. In others, docetaxel
will be evaluated in combination with 5-FU, in continuous infusion or as
a bolus, and with cisplatin.
This overview of the clinical development of docetaxel summarizes some
of the combination chemotherapy studies that have been conducted or are
ongoing. The challenge is not only to find effective combinations, strategies,
and regimens, but also to determine the optimal role for this agent in
relation to many other active agents in development today.
Early results from phase I combination chemotherapy studies in metastatic
or advanced disease demonstrate manageable toxicity at all dose levels
of docetaxel (25 to 100 mg/m²). The most frequent hematologic toxicity
was neutropenia, the incidence of infection was low, and there was generally
no significant cardiotoxicity. Response rates were observed in all studies,
ranging from 70% to 90%.
1. Data on file. Rhône-Poulenc Rorer Pharmaceuticals, Inc., Collegeville,
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