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Docetaxel/Doxorubicin/Cyclophosphamide in the Treatment of Metastatic Breast Cancer

Docetaxel/Doxorubicin/Cyclophosphamide in the Treatment of Metastatic Breast Cancer

ABSTRACT: Preliminary results from phase I trials suggest that the use of docetaxel (Taxotere) and doxorubicin (Adriamycin) is a well tolerated and highly active combination regimen for patients with metastatic breast cancer. The maximum tolerated dose of this combination was 50 mg/m² of doxorubicin given as an intravenous bolus followed 1 hour later with 75 mg/m² of docetaxel given as a 1-hour intravenous infusion. Because cardiotoxicity was not observed with this combination, we added cyclophosphamide (Cytoxan, Neosar) in a phase II trial to determine the antitumor activity and tolerability of this 3-drug combination as first-line therapy in patients with metastatic breast cancer. Preliminary results from this study indicate that the Taxotere/Adriamycin/Cyclophosphamide (TAC) combination produces response rates of up to 80%. However, frequent grade 4 neutropenia was seen in 68% of cycles, febrile neutropenia in 5.5% of cycles, and grade 3 to 4 infection in .8% of cycles. Cardiac toxicity was rare, with 1 case of reversible congestive heart failure (2%), which occurred 2 months after completion of chemotherapy. These preliminary data show that TAC is highly active and that docetaxel did not significantly increase the cardiotoxicity of doxorubicin. Phase III studies in both the first-line and adjuvant settings are warranted. [ONCOLOGY 11(Suppl 8):37-41, 1997]

Introduction

The integration of the taxanes in combination chemotherapy regimens
for a variety of cancers, including metastatic breast cancer, is becoming
a fundamental therapeutic approach in oncology. In patients with anthracycline-resistant
metastatic breast cancer, 100 mg/m² of Taxotere (docetaxel) administered
as a 1-hour intravenous infusion once every 3 weeks produced overall response
rates of up to 57%.[1,2] This lack of cross-resistance, in addition to
the substantial antitumor activity of both docetaxel and doxorubicin (Adriamycin)
provides the rationale for investigating this combination in patients with
metastatic breast cancer.

Kalla and colleagues[3] recently reported that an intravenous bolus
dose of 50 mg/m² of doxorubicin followed by 75 mg/m² of docetaxel
administered as a 1-hour infusion once every 3 weeks, without granulocyte
colony-stimulating factor support (G-CSF) (filgrastim [Neupogen]), produced
a response rate of 90% in patients with metastatic breast cancer. The most
encouraging finding from this trial, as well as from a trial by Itoh and
colleagues,[4] was the lack of clinically significant cardiac toxicity.

Kalla et al[3] found that none of the 42 patients treated with this
combination developed congestive heart failure, which typically occursat
a rate of 3% to 4% in patients who receive a cumulative dose of 450 mg/m²
of doxorubicin single-agent therapy.[5-7] This is in contrast to the findings
observed with the combination of doxorubicin and paclitaxel (Taxol), as
reported by Gianni et al[8] and Gehl et al,[9] who noted, respectively,
that 18% and 20% of patients with metastatic breast cancer developed reversible
congestive heart failure.

TAC for First-Line Therapy

Based on these preliminary data, our group performed a phase II trial
to determine the antitumor activity and tolerability of Taxotere and Adriamycin
with cyclophosphamide (TAC) as first-line therapy without prophylactic
G-CSF support, in patients with metastatic breast cancer.[10] In addition
to measuring response rate, duration of response, and time to progression,
we were interested in confirming the favorable toxicity profile--in particular,
the lack of cardiac side effects as reported previously[3,4] with the combination
of docetaxel and doxorubicin.

The inclusion criteria for this study consisted of patients with bidimensionally
measurable (80% of cases) or evaluable (20%) metastatic breast cancer who
had received no prior chemotherapy for metastatic disease and were anthracycline
naive. In addition, study participation was open to patients with a Karnofsky
performance status of at least 60% and who had normal left ventricular
ejection fractions on a multiple-gated acquisition scan at baseline.

The schema of treatment was doxorubicin, given at a dose of 50 mg/m²
as an intravenous bolus over 3 to 5 minutes, followed by 500 mg/m²
of cyclophosphamide, also as an intravenous bolus, and then 1-hour later,
75 mg/m² of docetaxel, administered as a 1-hour intravenous infusion.
This cycle was repeated once every 3 weeks. Patients also received 500
mg of oral ciprofloxacin (Cipro) twice daily on days 5 through 15 of each
cycle for prophylaxis against infection and 8 mg of dexamethasone twice
daily for 3 days, beginning the day prior to chemotherapy. As mentioned
previously, no prophylactic G-CSF was given in this trial.

Demographics and Treatment Discourse

Of 55 patients accrued in this trial, preliminary results are available
for 52 patients. Median patient age was 52 years (range: 33 to 70 years),
with a good median Karnofsky performance status of 90% (range: 60% to 100%).
A total of 31% of patients had received prior adjuvant chemotherapy, which
consisted exclusively of cyclophosphamide, methotrexate, and fluorouracil
(5-FU). The median number of organs involved by the disease was 3 (range:
1 to 6), with 3 or more organs involved in 52% of patients. Visceral disease
was seen in 60% of cases (liver involvement: 32% of patients). Bone metastases
were seen in 48% of patients.

To date, a total of 251 cycles are evaluable, with a median of 5 cycles
per patient (range: 1 to 8). The median cumulative doses were 254 mg/m²
(range: 49 to 419 mg/m²) for doxorubicin and 379 mg/m² (range:
75 to 617 mg/m²) for docetaxel. The relative dose intensity was .99
for doxorubicin and .98 for docetaxel.

Antitumor Activity

To date, 38 patients are evaluable for response. In 31 patients with
measurable disease, the preliminary response rate is 80%, consisting of
2 complete responses and 23 partial responses (Table
1
). The overall response rate, which included 7 patients with evaluable
disease, was 74%. Overall, there were 3 cases of complete response and
25 cases of partial response. In addition, the objective response rate
of this combination was consistent across sites of involvement: liver (83%),
lung (76%), visceral disease (76%), and soft tissue (75%). The preliminary
activity of this combination is similar to that seen with other docetaxel/doxorubicin
combinations.[3]

Tolerability

A total of 49 patients were included in the preliminary safety evaluation.
As expected with a combination regimen consisting of 3 myelosuppressive
agents, grade 4 neutropenia was common, occurring in approximately 68%
of the cycles and 96% of patients (Table
2
). Febrile neutropenia, with or without sepsis, which appears to be
a more clinically relevant indicator of toxicity, occurred in 24.5% of
patients, but in only 5.5% of administered cycles. Similarly, grade 3 to
4 infections were noted in 4% of patients and .8% of cycles. Despite the
high incidence of grade 4 neutropenia, the median absolute neutrophil count
on day 21 of each cycle was greater than 2,000/mm³, which allowed
for the continuation of treatment without delay and with high dose intensity.

Interestingly, no grade 4 acute nonhematologic toxicities were noted.
Grade 3 nonhematologic toxicities were infrequent and consisted primarily
of nausea (8%), stomatitis (6%), and diarrhea (4%). Of the chronic nonhematologic
toxicities, severe asthenia was noted in 10% of patients and severe fluid
retention in 1%. The classical toxicities, such as fluid retention, hypersensitivity
reactions, skin toxicity, and nail changes, seen with Taxotere alone were
rarely seen with the TAC combination. This contrasts with the toxicity
profile seen with 100 mg/m² of docetaxel in single-agent chemotherapy.
One could hypothesize the existence of a partial threshold of toxicity
between 75 and 100 mg/m² of docetaxel, which could favor the use of
TAC.

Evaluation of cardiotoxicity was a primary endpoint in this study. There
were no cases of congestive heart failure in the 35 patients who received
doxorubicin as a median cumulative dose of less than 360 mg/m². Of
the 14 patients who received a cumulative dose of more than 360 mg/m²,
1 patient (2%) developed congestive heart failure, which occurred 60 days
after completing the combination regimen. Overall, only 1 patient had an
asymptomatic reduction of left ventricular ejection fraction on multiple-gated
acquisition scan (Table 3).

The low incidence of clinical cardiotoxicity observed with the docetaxel/doxorubicin
combination in this trial is consistent with the results from earlier phase
I trials (Table 4).[3,11] These results
suggest that the addition of docetaxel to doxorubicin does not appear to
increase the incidence and severity of cardiotoxicity typically seen with
doxorubicin used as a single-agent[12] or with the 5-FU/doxorubicin/cyclophosphamide
regimen.[13] This contrasts with the apparent increase in congestive heart
failure reported with the addition of paclitaxel to doxorubicin in patients
with metastatic breast cancer.[8,9] Until further trials are performed,
one can only speculate as to why there appears to be a difference between
these two taxanes with respect to cardiotoxicity when combined with doxorubicin.

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