Doxorubicin has long been recognized as one of the most effective single
agents in the treatment of metastatic breast cancer, and doxorubicin combinations
are among the most active in advanced or metastatic disease. Docetaxel
(Taxotere) is highly active as a first- or second-line agent in the same
setting. Moreover, there is no clinical cross-resistance between the
These observations were the rationale for a feasibility study using
the two drugs in combination.[4,5] The objectives of the study were to
ascertain the dose-limiting toxicity, the maximum tolerated doses of these
drugs in combination, and the recommended doses for future phase II and
III trials, and to establish a safety profile of this combination therapy.
To be eligible, patients had to have metastatic breast cancer with measurable
and/or evaluable disease. Other criteria included no prior chemotherapy
for metastatic disease and a World Health Organization performance status
2 or less. Prior chemotherapy was allowed only if it occurred at the adjuvant
stage, at least 1 year before entry into the study, with a cumulative dose
of less than 300 mg/m² of doxorubicin, less than 500 mg/m² of
epirubicin, or less than 500 of mg/m² pirarubicin. Patients were required
to have normal baseline left-ventricular ejection fraction; during the
trial, ejection fraction was monitored every two cycles, and then every
cycle after a cumulative dose of anthracycline 400 or more mg/m² was
Every 3 weeks, doxorubicin was administered to outpatients as an intravenous
bolus over 15 minutes, followed after 1 hour by docetaxel as a 1-hour infusion.
No prophylactic supporting granulocyte colony-stimulating factor (G-CSF,
filgrastim [Neupogen]) was used.
Doxorubicin doses increased from 40 mg/m² at levels I and II, to
50 mg/m² at levels III through V, and to 60 mg/m² at level VI
(Table 1). Docetaxel doses increased from
50 mg/m² at level I, to 60 mg/m² at levels II and III, 75 mg/m²
at level IV, 85 mg/m² at level V, and dropped to 60 mg/m² at
level VI. Cumulative doses were monitored, and doxorubicin administration
was stopped at a cumulative dose of 550 mg/m².
To avoid hypersensitivity reactions, patients received prophylactic
premedication consisting of dexamethasone, cetirizine (an H1-blocker),
ranitidine, and Tanakan (ginkgo-biloba extracts) beginning on the day of
first infusion, and continuing throughout treatment until the first symptoms
of fluid retention appeared.
At least three patients were included at each dose level and followed
for a minimum of 3 weeks before escalation to the next dose level. If a
dose-limiting toxicity was noted in a patient, three more patients were
included at that level, and the average maximum tolerated dose was determined.
Maximum tolerated dose was defined if a dose-limiting toxicity was observed
in 2 of 3 or 3 of 6 patients.
Dose-limiting toxicity was defined as grade 4 neutropenia lasting more
than 7 days, febrile neutropenia lasting more than 3 days, grade 4 thrombocytopenia,
grade 3 or 4 infection, and any grade 3 or 4 adverse event except anemia.
The recommended dose for the phase II study is the highest dose that can
be safely administered to a patient. Usually it is chosen as the dose level
below the maximum tolerated dose.
A total 42 patients were entered into the study. Patients were characterized
by a high prevalence of visceral involvement (79%). The majority of the
patients (60%) had had prior adjuvant chemotherapy, with 52% receiving
an anthracycline-containing regimen. The prior median cumulative dose of
anthracycline was 152 mg/m² (range, 82 to 287 mg/m²).
Hematologic Adverse Events
The most frequent grade 3 and 4 toxicity was neutropenia. With the exception
of the lowest dose level, grade 4 neutropenia occurred in more than 70%
of cycles, with a median duration of 5 days (Table
Febrile neutropenia occurred in less than 10% of cycles (30/314 cycles).
One patient at level IV and two patients at level V developed a grade 3
or 4 infection (sepsis; Table 2). The
maximum tolerated doses were defined as doxorubicin, 50 mg/m², and
docetaxel, 85 mg/m², with sepsis as the dose-limiting toxicity occurring
in 3 of 42 patients. The recommended doses were defined as 50 mg/m²
of doxorubicin and 75 mg/m² of docetaxel, or 60 mg/m² on both
drugs on day 1 every 3 weeks, without G-CSF support.
Nonhematologic Adverse Events
Nonhematologic toxicity was mild, with no grade 3 or 4 adverse events.
There were no cases of severe fluid retention, although the median cumulative
dose of docetaxel was 610 mg/m² (range, 199 to 1,010 mg/m²).
Patients were carefully monitored for cardiotoxicity. At a median of
18.4 months of follow-up, only four patients had abnormal grade 1 cardiac
function, but all were asymptomatic; no congestive heart failure was observed,
although 23 patients needed a cumulative dose of doxorubicin more than
360 mg/m². No patient had to leave the study because of cardiac toxicity.
Although this was a phase I study, all 42 patients were evaluable for
response. Responses were observed at all dose levels. Response rates were
higher at dose levels III to V (80% to 90%). Response rates were also high
in patients whose disease had metastasized to the liver (82%). The median
follow-up of 18.4 months (range, 9.0 to 28.3 months) was not sufficient
to assess median duration of response or time to progression. Median survival
has not been reached, but 9 patients (21.4%) have died, and 33 patients
The results of five phase I studies of paclitaxel (Taxol)/doxorubicin
combination therapy in a total of 122 patients with advanced breast cancer
are summarized in Table 3. In the first
three studies, paclitaxel was administered by a prolonged (72- or 24-hour)
infusion, while doxorubicin dosing varied from a bolus to a 48- or 72-hour
infusion.[1-3,6] Administering paclitaxel as a 24-hour infusion before
doxorubicin resulted in sequence-dependent toxicity, consisting of an increased
incidence of severe mucositis and neutropenia. Similarly, giving both drugs
simultaneously in a 72-hour infusion caused a high, schedule-dependent
incidence of thrombocytopenia and typhlitis.
The response rates to these regimens were high, from 42% to 94% overall.
However, the complete response rate was less than 10%. Two of the studies
demonstrated that using shorter administration (3-hour) periods for both
drugs permitted higher dose intensity, with paclitaxel doses as high as
200 mg/m² and doxorubicin at 60 mg/m².[1,6,7] This resulted in
very good response rates. The 94% overall response rate of Gianni et al
included 40% complete responses in a chemotherapy-naive patient population.
However, these higher dosages were accompanied by an increase in cardiomyopathy,
which occurred in as many as 20% of patients.
In the current study, the maximum tolerated doses were defined as 50
mg/m² of doxorubicin and 85 mg/m² of doctaxel. The dose-limiting
toxicity was sepsis, occurring in two of five patients. The only grade
3 or 4 adverse event was neutropenia. There was no congestive heart failure,
significant decrease in left-ventricular ejection fraction, or discontinuation
of treatment because of fluid retention.
This study did not use G-CSF; an increase in dose intensity of this
combination might be possible if G-CSF were added to the regimen to control
febrile neutropenia. The recommended doses were defined as 75 mg/m²
of docetaxel and 50 mg/m² of doxorubicin, or 60 mg/m² of both
drugs on day 1 every 3 weeks, without G-CSF support. Responses were observed
at all dose levels.
The recommended doses used in this study demonstrated an acceptable
safety profile; ie, an acceptable incidence and severity of febrile neutropenia,
with no grade 3 or 4 toxicity or severe infection. A phase II trial is
underway, and an ongoing phase III study is investigating whether the doxorubicin/docetaxel
combination is more effective than doxorubicin/cyclophosphamide (Cytoxan,
1. Fisherman JS, McCabe M, Noone M, et al: Phase I study of Taxol, doxorubicin,
plus granulocyte-colony stimulating factor in patients with metastatic
breast cancer. Monogr Natl Cancer Inst 15:189-194, 1993.
2. Holmes FA, Frye D, Valero V, et al: Phase I study of Taxol (T) and
doxorubicin (D) with G-CSF in patients (pts) without prior chemotherapy
(CT) for metastatic breast cancer (MBC) (abstract). Proc Annu Meet Am Soc
Clin Oncol 11:A66, 1992.
3. Sledge GW Jr, Robert B, Sparano JA, et al: Paclitaxel (Taxol)/doxorubicin
combinations in advanced breast cancer: The Eastern Cooperative Oncology
Group experience. Semin Oncol 21(5; suppl 8):15-18, 1994.
4. Gruia G, Misset S, Giachetti S, et al: A phase I-II study of Taxotere
(TXTR) in combination with adriamycin (AD) as first line chemotherapy (CT)
in patients with metastatic breast cancer (MBC) (abstract 258). Proc Am
Soc Clin Oncol 14:140, 1995.
5. Kalla S, Bourgeois H, Gruia G, et al: Docetaxel (D) in combination
with doxorubicin (Dx) as 1st line CT of metastatic breast cancer (MBC):
A Phase I dose finding study-final results (abstract 5990). Ann Oncol 7(suppl
6. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion
in combination with bolus doxorubicin in women with untreated metastatic
breast cancer: High antitumor efficacy and cardiac effects in a dose-finding
and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
7. Dombernowsky P, Gehl J, Boesgaard M, et al: Treatment of metastatic
breast cancer with paclitaxel and doxorubicin. Semin Oncol 22(6: suppl