Anthracyclines, such as doxorubicin and epirubicin
(Ellence), and taxanes, such as paclitaxel (Taxol) and docetaxel (Taxotere), are
the most active cytotoxic agents for the treatment of metastatic breast cancer.
Because of the high level of activity and the lack of complete cross-resistance
between these two drug classes, several trials have been performed to evaluate
the feasibility and the toxicity of anthracycline/taxane combinations. In
patients who had not previously received chemotherapy, the combination of
doxorubicin and paclitaxel has been extremely active, inducing an overall
response rate of approximately 90% and a complete response rate (CR) as high as
41%.[1-4] Moreover, the combination of epirubicin and paclitaxel has resulted in
an interesting level of activity in previously untreated metastatic breast
cancer patients, who achieved an overall response rate of 84% and a CR rate of
Despite this high level of activity, chemotherapy for patients
with metastatic breast cancer is still considered palliative. A strategy that
may improve outcome for such patients is to increase the complete response to
first-line chemotherapy. Data indicate that only complete responders have the
potential to survive long-term.[6,7] Therefore, achieving CR is particularly
important. One possible way to increase the percentage of patients achieving CR
is the addition of an active drug with a different mechanism of action and
Good candidates for such treatments are the antimetabolites, and
one in particular is gemcitabine (Gemzar), a pyrimidine nucleoside analog.
Gemcitabine demonstrated an interesting level of activity with a good toxicity
profile when used as a single agent in the treatment of advanced breast cancer
patients. The overall response rate was up to 37% in patients who had
not previously received chemotherapy and 28% in previously treated
Based on these findings, we performed a phase II study of the
gemcitabine-epirubicin-paclitaxel (GET) combination as first-line therapy for
metastatic breast cancer. Study goals were to determine the rates of CR and
objective response as well as progression-free survival and overall survival.
The treatment included gemcitabine at 1,000 mg/m2 on days 1 and 4, epirubicin at
90 mg/m2 on day 1, and paclitaxel at 175 mg/m2 on day 1. Treatment was repeated
every 3 weeks for up to eight courses.
A total of 36 patients were enrolled in the trial. Median age
was 49 years (range: 25-64 years); median Eastern Cooperative Oncology Group
(ECOG) performance status was 0 (range: 0-2); hormonal status was positive in
20 patients (56%), negative in 9 (25%), and unknown in 7 (19%). Eighteen
patients had received previous adjuvant treatment that included epirubicin in
two cases. In these patients, the previous cumulative epirubicin dose was 360
mg/m2. Two patients had previously received hormonal therapy for metastatic
disease. Sixteen patients (44%) had at least three metastatic sites and 23
patients (64%) had dominant visceral disease.
The GET regimen was well tolerated. Dose delays were necessary
in 24% of courses and dose reductions in 14%. Eleven patients (31%) had a CR and
22 patients (61%) had a partial response (PR). The overall response rate was 32%
after two treatment courses and increased to 92% (95% confidential interval,
77.53% to 98.25%) after six or more courses.
Twenty-five patients who had responded to the GET regimen then
received high-dose chemotherapy with peripheral blood stem cell support. Of
these 25, 13 patients who had achieved a PR (n = 10) or stable disease (SD)
(n = 3) after six GET courses, received one course of high-dose idarubicin
(Idamycin) (40 to 70 mg/m2). Ten of 13 patients who did not achieve a CR after
idarubicin treatment received one additional course of thiotepa (Thioplex) (600
mg/m2), plus melphalan (Alkeran) (160 mg/m2). Another 12 patients (5 who had
achieved a PR and 7 who had achieved a CR) after six GET courses received one
course of thiotepa plus melphalan.
A conversion to a better response was observed in 39% of the
patients, leading to an overall response rate of 97%, including 47% CR. After a
median of 12 months of follow-up, the median progression-free survival was 19.4
months. Median overall survival has not yet been reached (Figure
Another possible strategy to improve outcome of patients with
metastatic breast cancer is to try to maintain the obtained response by
prolonging the duration of chemotherapy. Results of several randomized phase III
studies have indicated that prolonged administration of chemotherapy results in
a longer time to disease progression, and may improve survival and quality of
The importance of chemotherapy duration has also been confirmed
by clinical data showing that although most metastatic breast cancer patients
who respond to anthracycline/taxane combinations do so within four treatment
courses, the best response is often reached after six or more courses.
Furthermore, the proportion of CR has been shown to increase when chemotherapy
is prolonged with administration of single-agent paclitaxel after an objective
response is achieved with the doxorubicin/paclitaxel combination.
The potential benefit of prolonging chemotherapy administration
is supported by the breast cancer practice guidelines recently issued by the
National Comprehensive Cancer Network (NCCN). These guidelines recommend
continuing chemotherapy until disease progression in patients with
estrogen-receptor- and progesterone-receptor- tumors, symptomatic visceral
metastases, or disease refractory to hormonal therapy.
Management of metastatic breast cancer, however, requires a
balance between the potential benefits of prolonging chemotherapy and toxicities
induced by such treatment. In particular, prolonged treatment with the
paclitaxel/anthracycline combination, the most active drugs in advanced breast
cancer, is not feasible because of cumulative, anthracycline dose-related
cardiotoxicity. On the other hand, paclitaxel may be a good candidate for
maintenance therapy due to its favorable toxicity profile.
We are conducting a phase III, multicenter randomized trial
(MANTA) to evaluate whether paclitaxel maintenance treatment improves time to
disease progression and overall survival in metastatic breast cancer patients.
Patients first receive induction treatment with one of the following regimens:
epirubicin at 90 mg/m2 plus paclitaxel at 200
mg/m2 every 21
doxorubicin at 50 mg/m2 followed 16 hours later by
paclitaxel at 200 mg/m2 every 21 days; or
doxorubicin at 50 mg/m2 day 1 plus paclitaxel at 200
day 2 every 21 days for eight courses.
Following induction therapy, only responding patients are
randomly assigned to receive an additional eight courses of paclitaxel at 175
mg/m2 every 21 days or no further treatment. The trial will accrue 400 patients.
Characteristics of the 243 patients enrolled so far are:
median age, 55 years;
median performance status, 0;
29% of patients are premenopausal;
58% are estrogen-receptor positive;
50% have previously received adjuvant chemotherapy and 19%
have received hormonal treatment for metastatic disease;
dominant metastatic sites are viscera 64%, bone 21%, and
soft tissue 15%.
Another potential strategy to improve outcome of patients with
advanced breast cancer is to re-treat patients whose disease progresses after
having received an anthracycline-containing regimen with the same drug. To this
end, we have analyzed the effects of anthracycline-containing adjuvant treatment
on overall response rate, progression-free survival, and overall survival of
metastatic breast cancer patients who receive epirubicin-containing first-line
A total of 312 patients with metastatic breast cancer who
received first-line epirubicin-containing chemotherapy were included in the
analysis. Of these, 182 patients received FEC (fluorouracil, epirubicin,
cyclophosphamide [Cytoxan, Neosar]) (group A) and 130 patients received
epirubicin plus paclitaxel (group B).
In group A, 39 of 182 patients had received anthracyclines in
the adjuvant setting (25 FEC; 14 doxorubicin). The median patient age was 54
years (range: 25 to 72 years); median performance status was 0 (range: 0 to 1);
and 23% of patients were estrogen-receptor positive. Sites of metastatic disease
were viscera in 44%, bone in 23%, and soft tissue in 33% of patients. Among
patients who had received adjuvant anthracyclines, the overall response rate was
44%, with a median progression-free survival of 6.6 months and median overall
survival of 15.8 months.
In group B, 27 of 130 patients had received anthracyclines in
the adjuvant setting (3 FAC [fluorouracil, Adriamycin (doxorubicin), and
cyclophosphamide (Cytoxan, Neosar)],
one Abeloff regimen, 23 FEC). The median patient age was 52 years (range: 25 to
72 years); median performance status was 0 (range: 0 to 2); and 34% of patients
had estrogen-receptor-positive tumors. Dominant sites of metastatic disease
were viscera in 64% of patients, bone in 30%, and soft tissue in 6%. The overall
response rate was 85%, median progression-free survival was 12.6 months, and
median overall survival was 24.7 months. These response rates apply only to
those patients who had received adjuvant anthracycline therapy.
Among the 246 patients who had not received an anthracycline in
the adjuvant setting, 143 received first-line FEC and had an overall response
rate of 43%, median disease-free survival of 9 months, and median overall
survival of 15 months. Another 103 patients received first-line
epirubicin/paclitaxel and had an overall response rate of 84%, median
disease-free survival of 15 months, and overall survival of 27 months (Figure
In conclusion, these data indicate that epirubicin is active in
metastatic breast cancer patients who have previously received anthracycline
treatment in the adjuvant setting. Furthermore, the toxicity profile of
epirubicin is favorable in that the risk of developing congestive heart failure
is low up to a cumulative dose of 990 mg/m2.
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