The anthracyclines and the taxanes have been shown to be the
most active single-agent therapies for breast cancer. The incorporation of
anthracyclines in combination regimens has increased response rate, remission
duration, and survival of patients with advanced disease. Approximately 20%
of patients remain disease-free 10 years after achieving a complete response
(CR). Moreover, a recently published meta-analysis of adjuvant
polychemotherapy showed that anthracycline-containing regimens were moderately
superior to non-anthracycline regimens.
The use of anthracyclines is limited, however, by cumulative
dose-related cardiotoxicity. Among the possible strategies to decrease this
life-threatening toxicity, the development of epirubicin (Ellence), a
doxorubicin analog, is of particular interest. Epirubicin retains antitumor
activity comparable to that of doxorubicin, but is less cardiotoxic (although
it does not eliminate cardiotoxicity) and less myelotoxic than the parent
compound at equimolar doses. The need to reduce or avoid cardiac toxicity is
evidenced by results of studies of anthracycline/taxane combinations.
The combination of doxorubicin plus paclitaxel (Taxol) proved to
be very active as first-line chemotherapy for advanced breast cancer, with an
overall response rate of approximately 90% and CR rates as high as 41%.[6,7] The
combination of doxorubicin plus paclitaxel, however, was associated with
enhanced cardiotoxicity, which became apparent at cumulative doxorubicin doses
significantly lower than those recommended when doxorubicin is administered
alone or combined with other drugs. Two independent studies by Gianni and
Dombernowsky reported a 20% incidence of congestive heart failure (CHF)
among metastatic breast cancer patients receiving the doxorubicin plus
To maintain the high activity of this combination while
ameliorating the cardiac toxicity, we have studied an anthracycline/paclitaxel
combination that replaced doxorubicin with epirubicin. Study end points were to
determine the maximum tolerated dose (MTD) of paclitaxel over 3 hours with a
fixed dose of epirubicin, and to evaluate the toxicity and activity in
previously untreated metastatic breast cancer patients.
Fifty patients were enrolled in the trial. The MTD was reached
with doses of epirubicin at 90 mg/m2 plus paclitaxel at 200 mg/m2. This
combination was found to be feasible, with a low rate of cardiotoxicity (6%
incidence of CHF). The overall response rate was 84% and CR rate was 19%.[11-13]
The excellent cardiac tolerability of this combination compared
with that associated with doxorubicin/paclitaxel cannot be explained solely
based on epirubicin’s lower rate of cardiotoxicity. Another possible
explanation may include better patient selection. Moreover, recent data from
Gianni and our group showed that coadministration of epirubicin and paclitaxel
induces an increase in glucuronidation of epirubicin, leading to increased
urinary elimination and decreased plasma levels of epirubicinol, the cardiotoxic
metabolite of epirubicin.[14,15]
In contrast, coadministration of doxorubicin with paclitaxel
causes nonlinear disposition of doxorubicin, which results in increased plasma
concentrations of doxorubicin and its main metabolite doxorubicinol, a major
determinant of myocardial damage.[15,16] Thus, the pharmacokinetic interactions
of anthracyclines/paclitaxel are different depending on the particular
We conducted a trial of epirubicin plus paclitaxel to evaluate
the incidence of clinically significant cardiac toxicity and to identify
patients at high risk of developing CHF. We thought it would be particularly
important to identify patients for whom the benefits of chemotherapy might be
negated by the occurrence of CHF.
In this study of 105 patients with metastatic breast cancer,
none developed CHF during the treatment, but nine patients (9%) developed CHF
after cumulative epirubicin doses of 1,080 mg/m2 (n = 4), 720 mg/m2 (n = 2), 630
mg/m2 (n = 1), and 540 mg/m2 (n = 2). One of the patients who developed CHF
after epirubicin cumulative doses of 540 mg/m2 had received high-dose
consolidation chemotherapy. Median time to manifestation of cardiac symptoms was
3 months after completion of chemotherapy (range: 3 to 6 months).
The incidence of CHF was 13% in patients with pre-existing
cardiac risk factors (age, diabetes, hypertension, previous radiotherapy to the
chest) and 4% in patients without these risk factors. This analysis showed that
the incidence of CHF after epirubicin/paclitaxel treatment is low up to
cumulative epirubicin doses of
990 mg/m2, thus allowing safe administration of this regimen even in patients
who may have received epirubicin in the adjuvant setting. The risk of developing
CHF does, however, increase when the cumulative epirubicin dose exceeds 990 mg/m2 and when additional cardiac risk factors are present.
Overall, no clear role for the proposed risk factors for
cardiotoxicity was observed in this analysis. Nine patients developed CHF, 7
(13%) of 54 patients with and 2 (4%) of 51 patients without risk factors.
Based on the pharmacokinetic and pharmacodynamic interactions
that occur when anthracyclines and paclitaxel are administered together, we
wanted to examine the possibility that combinations of these agents result in
subadditive antitumor activity. In a phase III study (MIG 6), concomitant vs
sequential administration of epirubicin and paclitaxel are being compared in
patients with advanced breast cancer. The primary study end point is overall
response rate; secondary end points include CR rates, toxicity, quality of life,
pharmacoeconomic, and pharmacokinetic analyses.
To date, 112 patients have been enrolled, all of whom have been
evaluated for response. The overall response rate is 60% (CR rate, 13%), with a
median progression-free survival of 12.3 months, and a median overall survival
of 26.3 months.
Available data on use of docetaxel (Taxotere) in combination
with anthracyclines indicate that this regimen has antitumor activity similar to
that of paclitaxel/anthracycline combinations. The rationale for combining
epirubicin and docetaxel includes the high level of activity and tolerability of
each drug as a single agent, and preliminary evidence suggesting that
coadministration of epirubicin and docetaxel does not result in pharmacokinetic
interactions that lead to increased risk of cardiotoxicity.
Based on these data, we are conducting a phase I/II study of
epirubicin plus docetaxel as first-line chemotherapy for advanced breast cancer
patients. The purpose of the study is to evaluate the MTD of docetaxel in
combination with epirubicin at two different dose levels (75 and 90 mg/m2),
administered every 21 days to breast cancer patients with locally advanced
(LABC) or metastatic (MBC) disease.
At the time of this report, 58 patients (35 LABC and 23 MBC)
have been treated and are evaluable for toxicity and response. Grade 4
neutropenia occurred in 69% of cycles, with fever in 11%. Dose-limiting
toxicities were febrile neutropenia and grade 4 neutropenia lasting more than 7
The following MTDs have been identified: epirubicin at 90 mg/m2
plus docetaxel at 60 mg/m2, epirubicin at 75 mg/m2 plus docetaxel at 80
and epirubicin at 90 mg/m2 plus granulocyte-colony colony stimulating factor
(G-CSF). The recommended doses for subsequent studies are epirubicin at 75 mg/m2/docetaxel at 80
mg/m2 without G-CSF. The overall response rate was 73% (7%
complete and 66% partial response.
The high level of activity of anthracycline/taxane regimens in
patients with metastatic breast cancer has prompted investigations of the role
of these regimens in the adjuvant setting.
Italian investigators are performing the Gruppo Oncologico
Nord-Ouest (GONO)-MIG 5 multicenter randomized trial in which epirubicin plus
paclitaxel (Taxol) (ET) is being compared with fluorouracil, epirubicin, and
cyclophosphamide (Cytoxan, Neosar) (FEC) as adjuvant chemotherapy for
node-positive breast cancer patients. Because the potential for cardiotoxicity
is an important issue in the adjuvant setting, the study includes an analysis of
the incidence of CHF.
A total of 631 patients have been evaluated, of whom 314 have
received FEC and 317 ET. Follow-up time exceeds 1 year in 92% of patients. Grade
1 (World Health Organization [WHO] criteria) cardiotoxicity was reported in five
patients receiving FEC, which occurred from 65 to 127 days after randomization,
and in four patients receiving ET, 23 to 29 days after randomization. One
patient receiving ET had grade 2 cardiotoxicity after the second chemotherapy
course, consisting of sinus block with syncope followed by atrial fibrillation
that lasted 24 hours.
Of note, no episodes of CHF were observed among patients
receiving the ET combination. In addition to epirubicin’s advantages related
to reduced potential for cardiotoxicity, the excellent cardiac tolerability of
the adjuvant ET regimen might be related to the low cumulative epirubicin dose
(ie, 360 mg/m2) and the good performance status of patients in this trial.
However, because epirubicin/paclitaxel combinations have been associated with a
low incidence of cardiotoxicity in patients with metastatic breast cancer, the
GONO-MIG 5 investigators have recommended continued clinical monitoring during
study treatment and follow-up.
The combination of epirubicin and taxanes is feasible and
maintains an interesting level of activity. Moreover, cardiotoxicity, which was
an important complication of concomitant doxorubicin and paclitaxel treatment,
is not a major issue when epirubicin is used instead of doxorubicin. This
observation should be considered when planning clinical trials in the adjuvant
and neoadjuvant settings.
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