Docetaxel (Taxotere) and doxorubicin (Adriamycin) are considered 2 of
the most active chemotherapeutic agents for patients with metastatic breast
cancer. When used as first-line therapy, single-agent docetaxel, administered
at a dose of 100 mg/m² as an intravenous infusion over 1-hour once
every 3 weeks, has produced response rates ranging from 57% to 69%.
At the same dose, docetaxel also has a high level of activity in second-
and third-line regimens, as well as in anthracycline-resistant or -refractory
patients with metastatic breast cancer.[2,3]
Doxorubicin is widely considered the agent of choice for metastatic
breast cancer in first-line therapy. Response rates with doxorubicin in
first-line regimens range from 29% to 43%, and the median survival time
is approximately 2 years. The rationale for using docetaxel and doxorubicin
in combination for patients with metastatic breast cancer includes the
facts that doxorubicin-containing regimens are among the most active and
that there is at least a partial clinical cross-resistance between the
Two phase I trials, one being performed in France[5,6] and the other
in Japan, characterize the ongoing ef forts to investigate the potential
benefit of docetaxel/doxorubicin combination regimens in patients with
metastatic breast cancer. Both trials are designed to determine the dose-limiting
toxicity, the maximum tolerated dose, the recommended dose for phase II
and III trials, and the safety profile of the combination.
The study by Itoh and colleagues also examined the clinical and pharmacokinetic
impact of the sequence of administration of docetaxel and doxorubicin.
Inclusion criteria for study participation in both trials included patients
with measurable and/or evaluable disease who had not received prior chemotherapy
for metastatic disease and no prior adjuvant chemotherapy for at least
In the French study,[5,6] prior adjuvant anthracycline therapy was allowed,
provided patients had received a cumulative dose that was less than or
equal to the following: 300 mg/m² of doxorubicin, 500 mg/m² of
epirubicin, or 500 mg/m² of tetrahydropyranyl (THP) doxorubicin. In
the Japanese study, no anthracycline-based chemotherapy was allowed,
and Eastern Cooperative Oncology Group (ECOG) performance status had to
be less than 3. Patients were also required to have normal baseline left
ventricular ejection fraction levels by multiple-gated acquisition scan.
In the French study,[5,6] the treatment plan included doxorubicin administered
intravenously as a bolus over 15 minutes, followed 1 hour later by docetaxel,
which was given by intravenous infusion over 1 hour. This schedule was
later repeated every 3 weeks on an outpatient basis. A total of 6 dose
levels of doxorubicin/docetaxel were studied: 40 mg/m² of doxorubicin/
50 mg/m² of docetaxel (level 1); 40 mg/m²of doxorubicin/60 mg/m²
of docetaxel (level 2); 50 mg/m² of doxorubicin/60 mg/m²of docetaxel
(level 3); 50 mg/m² of doxorubicin/75 mg/m² of docetaxel (level
4); 50 mg/m² of doxorubicin/85 mg/m² of docetaxel (level 5);
60 mg/m² of doxorubicin/60 mg/m² of docetaxel (level 6) (Table
Patients did not receive prophylactic granulocyte colony-stimulating
factor (G-CSF) (Granocyte). Premedication for the prevention of hypersensitivity
reactions and fluid retention included 8 mg of dexamethasone administered
every 6 hours for 3 days, beginning the day prior to chemotherapy; 10 mg
of cetirizine (Zyrtec) administered 7 hours and 1 hour before the infusion
with docetaxel; and 300 mg of ranitidine (Zantac) administered once daily
for 3 days, starting 1 day prior to chemotherapy.
Currently, there are 42 patients entered in this trial. Median age is
48 years (range: 30 to 69 years). A total of 24 of 42 patients (57%) had
received prior adjuvant chemotherapy, of whom 22 of 24 (92%) received anthracycline-based
adjuvant chemotherapy. Of these 42 patients, 79%, had visceral involvement,
36% with 2 or more metastatic sites, 43% with liver involvement, and 41%
with bone lesions.
Overall, the median number of cycles of the combination administered
was 7 (range: 2 to 10). The overall median cumulative dose of doxorubicin
was 310 mg/m² (range: 99 to 534 mg/m²) and of docetaxel 423 mg/m²
(range: 149 to 707 mg/m²). At all dose levels, the most frequent toxicity
was neutropenia (Table 1). Although grade
4 neutropenia occurred in more than 73% of the cycles for dose levels 2
through 6, febrile neutropenia occurred in less than 14% of the cycles.
Febrile neutropenia was complicated by infection in 2 patients at dose
level 5, thus defining the maximum tolerated dose as 50 mg/m² of doxorubicin
combined with 85 mg/m² of docetaxel without prophylactic G-CSF support.
The nonhematologic toxicities associated with the combination of doxorubicin
and docetaxel were minor, with maximum severity being a grade 2 or less.
The most common nonhematologic toxicities were those typically seen with
most chemotherapeutic regimens, namely, nausea, vomiting, diarrhea, and
stomatitis. Of particular note was the lack of severe fluid retention in
this study, with a mean cumulative dose of docetaxel of 460 mg/m²
and the lack of grade 3 mucositis. Moderate fluid retention was noted in
19% of the patients.
Decreased left ventricular ejection fraction was noted in 4 patients,
and no patient presented with congestive heart failure after a median follow-up
of 18 months and a median cumulative dose of doxorubicin of 392 mg/m²
(range: 240 to 559 mg/m²). No patients were discontinued from the
study, even though most of the patients (55%) had received doxorubicin
at cumulative doses greater than 360 mg/m².
The overall response rate across all dose levels was 72%. However, at
the dose level of 50 mg/m² of doxorubicin combined with 75 mg/m²
of docetaxel, the response rate was 90%. In addition, patients with metastasis
to the liver achieved a response rate of 83% at all dose levels.
Itoh and colleagues recently reported the preliminary results of
an ongoing trial that assessed the impact of alternating the sequence of
administration of doxorubicin and docetaxel when used in combination for
patients with advanced breast cancer. The treatment plan includes 4 dose
levels. For dose level 1, patients receive 50 mg/m² of docetaxel followed
by 40 mg/m² of doxorubicin for 1 cycle. In the second cycle, 40 mg/m²
of doxorubicin was administered first followed by 50 mg/m² of docetaxel.
Similarly, patients in dose level 2 receive 60 mg/m² of docetaxel
followed by 40 mg/m² of doxorubicin for 1 cycle. In the second cycle
of dose level 2, 40 mg/m² of doxorubicin is administered first, followed
by 60 mg/m² of docetaxel. In dose level 3, patients receive 50 mg/m²
of doxorubicin followed by 60 mg/m² of docetaxel. Patients in dose
level 4 receive 50 mg/m² of doxorubicin followed by 70 mg/m²
of docetaxel. The sequences in dose levels 3 and 4 are not switched.
Dose-limiting toxicity was defined as: grade 4 neutropenia for 7 days
or longer, grade 4 neutropenia for more than 3 days, accompanied by fever
associated with an infection, grade 4 thrombocytopenia; or any grade 3
or 4 nonhematologic toxicity, except alopecia, vomiting, and general malaise.
The maximum tolerated dose has not been reached for the sequence of
doxorubicin followed by docetaxel. Profound grade 4 neutropenia was noted
in 3 patients with the sequence of 60 mg/m² of docetaxel, followed
by 40 mg/m² of doxorubicin. Although the sequence of administration
did not affect the pharmacokinetic parameters of either drug, these preliminary
results suggest that drug sequence may play a role in the duration of neutropenia.
The authors noted that patient accrual is ongoing at dose level 2, with
the sequence of 50 mg/m² of doxorubicin followed by 60 mg/m²
Based on the results from the phase I trial by Dieras and colleagues,
the regimen of doxorubicin followed by docetaxel appears to be a very active
combination, with an overall response rate of 90% at the highest feasible
dose without G-CSF support.
The recommended dose and sequences for future phase II and III trials
is 50 mg/m² of doxorubicin followed by 75 mg/m² of docetaxel,
or 60 mg/m² of both drugs, once every 3 weeks without prophylactic
G-CSF support. In 10 patients at the former dose level, the response rate
Although asymptomatic abnormal left ventricular function was noted in
4 patients (and reversible in 3 patients), there were no cases of doxorubicin-related
congestive heart failure. This is of particular importance because retrospective
studies have estimated that the incidence of doxorubicin-related congestive
heart failure is 3% to 4% in patients who receive a cumulative dose of
450 mg/m² of doxorubicin as single-agent therapy.[8-10]
The incidence of congestive heart failure following the combined use
of doxorubicin and paclitaxel (Taxol) was reported by Gianni and colleagues.
These authors noted that reversible congestive heart failure occurred in
21% (range: 7% to 35%; 95% confidence interval) of patients who had received
a 3-hour infusion of paclitaxel combined with a bolus dose of doxorubicin.
Of the 6 affected patients 5 had received a total dose of 480 mg/m²
of doxorubicin, with the remaining 1 patient experiencing congestive heart
failure only after receiving a total dose of 120 mg/m².
The same cardiotoxicity profile was observed in another study of the
combination of paclitaxel and doxorubicin. Gehl et al reported that
50% of the patients developed an abnormal left ventricular ejection fraction,
resulting in congestive heart failure in 20% of the patients.
In summary, doxorubicin followed by docetaxel appears to be a promising
combination regimen for patients with untreated metastatic breast cancer.
Except for grade 4 neutropenia and/or its complications, no severe nonhematologic
toxicities were observed with this combination. Based on the high level
of activity noted, additional studies are warranted to determine the optimal
integration of docetaxel in combination with anthracyclines in the adjuvant
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