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Metastatic Breast Cancer: Experience with the Combination Paclitaxel Plus Epir
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Metastatic Breast Cancer: Experience with the Combination
Paclitaxel Plus Epirubicin
Review Article [1] | January 01, 1998
By Hans-Joachim Lück, MD [2]
This study evaluated the safety and feasibility of the combination of paclitaxel (Taxol) and
epirubicin, the 4¢-epimer of doxorubicin, in women with metastatic breast cancer. A total of 85
patients with histologically proven
Paclitaxel (Taxol) is one of the few active drugs for the treatment of metastatic breast cancer. One of
the most important observations made in the earliest studies of the drug by Holmes et al[1] and
Reichman et al[2] was that clinical resistance to doxorubicin does not predict resistance to
paclitaxel. This observation suggests the feasibility of evaluating the combination of paclitaxel and
anthracyclines, which are also active in metastatic breast cancer.
Holmes et al[3] performed a phase I study in which paclitaxel was administered as a 24-hour
intravenous infusion, followed by doxorubicin given as a 48-hour continuous infusion. The
dose-limiting toxicity in this study was mucositis, which occurred with relatively low doses of both
drugs. Sledge et al[4]described a phase I trial that used the same regimen but with the reverse
sequence. The doxorubicin infusion was followed, after 4 hours, by a 24-hour paclitaxel infusion. The
rate of severe mucositis associated with this schedule was very low. The maximum tolerated doses
were 50 mg/m² of doxorubicin and 150 mg/m² of paclitaxel.
Dombernowski et al[5] and Gianni et al[6a] reported high response rates in patients with previously
untreated metastatic breast cancer who received paclitaxel (via a 3-hour infusion) combined with
doxorubicin. In these studies, the main toxicities were neutropenia and febrile neutropenia. Both
studies described severe cardiac toxicities in 15% to 25% of patients. It was then showed that by
limiting the cumulative dose of doxorubicin to 360 mg/m² or administering the two drugs with a
more prolonged interval, the cardiac toxicity of the combination was limited to an incidence of
5%.[6b,6c]
Epirubicin, the 4′-epimer of doxorubicin, is as effective as its parent compound but less
cardiotoxic.[7] A literature search revealed eight trials in which doxorubicin and epirubicin were
compared in patients with metastatic breast cancer. In three trials, identical doses of doxorubicin
and epirubicin produced identical response rates.[8-10] In five others, the dose ratio of doxorubicin
to epirubicin was 1.4.[11-15] The response rate was similar in all of these trials, independent of dose
ratio. Mouridsen et al[16] reported that the two drugs have similar pharmacodynamics, antitumor
spectrum, and levels of clinical efficacy.
The aim of this phase II study was to evaluate the safety and feasibility of combining paclitaxel and
epirubicin in patients with metastatic breast cancer, focusing specifically on cardiac side effects.
Patients and Methods
Eligibility Criteria—Only patients with histologically proven metastatic breast cancer were recruited
to participate in this study. To be eligible, patients were not allowed to have received prior
chemotherapy for metastatic disease, but they could have received one prior regimen of adjuvant
chemotherapy or hormone therapy, or one palliative hormone therapy. If the patient had received
prior anthracycline therapy, the total allowable dose was 300 mg/m².
Other eligibility criteria included measurable metastasis and normal hematologic, renal, and hepatic
function, as well as age between 18 and 70 years and a life expectancy of more than 12 weeks.
Patients who did not meet these criteria were not eligible for the study. Patients with congenital
heart failure also could not participate.
Study Design—Patients were treated in two cohorts. Group A received epirubicin 60 mg/m² IV
infused over 1 hour, followed by paclitaxel 175 mg/m² IV infused over 3 hours. Group B received
epirubicin 90 mg/m² IV via a 1-hour infusion, followed by paclitaxel 175 mg/m² IV via a 3-hour
infusion. Both groups were premedicated with dexamethasone 20 mg PO for two doses, one dose 12
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Metastatic Breast Cancer: Experience with the Combination Paclitaxel Plus Epir
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hours and the other 6 hours before paclitaxel. In addition, patients received clemastine 2 mg IV, and
ranitidine 50 mg IV, 30 minutes before paclitaxel.
Left-ventricular ejection fraction was assessed prior to treatment and after every second cycle by
echocardiography or multiple-gated acquisition (MUGA) scanning.
Paclitaxel dose escalation (without granulocyte colony-stimulating factor support) was permissible to
a dose of 225 mg/m², in 25-mg/m² steps, as long as the neutrophil count nadir was ≥ 1 × 10 /L and
peripheral neuropathy was lower than World Health Organization (WHO) toxicity grade 2. In cases of
higher toxicity grades, the paclitaxel dose could be reduced to 135 or 110 mg/m².
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Results
Initially, 57 patients were enrolled in group A and 28 patients were enrolled in group B. The median
ages were 51 years (group A) and 55 years (group B), and the median Eastern Cooperative Oncology
Group (ECOG) performance index was 0. Most of the women in the two groups (62% of group A and
76% of group B) were postmenopausal and most had poorly differentiated tumors (63% of group A
and 74% of group B). Prior adjuvant chemotherapy had been administered to 51% of the patients in
group A and 36% of those in group B.
Ultimately, 43 patients in group A and 25 in group B were evaluable for response and toxicity. In
group A, 15 patients could not be evaluated for response; 12 of these patients had bone metastasis
only and two had received prior chemotherapy for metastatic disease. In group B, three patients had
bone metastasis with nonbone metastatic disease that was only evaluable but not measurable.
Nearly 20% of the patients had primary metastatic breast cancer with a large tumor at the primary
site. Table 1 summarizes the location of metastases. More than 80% of the patients had two or more
lesions (Table 2).
Toxicity
The main toxicity observed in both groups of patients was neutropenia, which reached WHO toxicity
grade 3 or 4 during 73% of the courses in group A and 93% of the courses in group B. No episodes of
febrile neutropenia developed in group A, and only two episodes occurred in group B.
Thrombocytopenia and anemia were observed during fewer than 1% of the courses (Table 3).
Alopecia developed in all patients who completed two or more cycles of therapy. No peripheral
neuropathy exceeded WHO grade 2, and grade 3 myalgia was reported in only 1% of the cycles.
Severe nausea and emesis were observed in 2% of the cycles (Table 4), and no case of mucositis
was described.
To date, no cardiac toxicity has been seen. Left-ventricular ejection fraction, assessed by
echocardiography or cardiac scintigraphy, did not change in any patient in group A. One patient in
group B showed a significant decrease (> 10%) in ejection fraction that was not accompanied by
clinical signs.
Dose Modification
In group A, 15 patients were able to tolerate escalation of the paclitaxel dose to 200 mg/m², and
further escalation to 225 mg/m² was possible in seven of these patients. In group B, dose escalation
to 200 mg/m² was possible in only one patient, and no patient could tolerate 225 mg/m². On the
other hand, severe neutropenia necessitated a dose reduction to 135 mg/m² in 11 group-A patients
and a subsequent reduction to 110 mg/m2 in four of these patients. Dose reduction to 135 mg/m²
was required in three group-B patients.
Response
Response was not the main end point of this study, but it is a principal concern of oncology
treatment. Results achieved in this poor-prognosis population are shown in Table 5. Overall response
was similar in the two groups. Escalation of paclitaxel dose was not associated with higher remission
rates. Similarly, paclitaxel dose reduction due to neutropenia had no apparent effect on remission
rates (Table 6). In 50% of patients who responded, remission was achieved after the second course
of treatment; 25% of patients had their best result after the fourth course; and the remaining 25% of
responses were seen after the sixth course.
The median follow-up time was 14.1 months in group A and 8.2 months in group B. The median
progression-free interval was 8.2 months in both groups, with a range of 5.3 to 11.3 months in group
A and 7.9 to 8.5 months in group B. When broken down according to response, the median
progression-free interval was 12.5 months (95% confidence interval [CI], 9.7 to 15.3 months) in
group A patients who attained a complete response and 8.1 months (95% CI, 6.7 to 10.3 months) in
those who had a partial response. In group B, the median progression-free interval for patients with a
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Metastatic Breast Cancer: Experience with the Combination Paclitaxel Plus Epir
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partial response was 8.2 months (95% CI, 7.8 to 8.5 months).
The median overall survival from study entry was 15.9 months (95% CI, 12.8 to 19 months) in group
A. In group B the median survival has not been reached.
Discussion
In this study, the combination of paclitaxel 175 mg/m² and epirubicin 60 or 90 mg/m² showed
remarkable efficacy against metastatic breast cancer. The overall response rates were 68% in group
A (treated with 60 mg/m² of epirubicin) and 68% in group B (given 90 mg/m² of epirubicin).
The combination of paclitaxel and epirubicin was generally well tolerated. The higher epirubicin dose
induced more severe neutropenia and one case of cardiotoxicity. Nonhematologic toxicities were
mild, and no cases of severe mucositis or peripheral neuropathy were reported.
Neither the higher epirubicin dose nor the modified paclitaxel doses altered progression-free
survival. The remission rates observed in the present study were lower than those reported in the
study by Gianni et al[6] in patients with no prior treatment except surgery. However, the
progression-free interval was in the same range as that observed by Gianni et al.
Based on the results of this study, in December 1996 the German AGO (Arbeitsgemeinschaft
Gynäkologische Onkologie) Breast Cancer Study Group initiated a phase III trial comparing the
combination of paclitaxel 175 mg/m² and epirubicin 60 mg/m² with the standard combination of
epirubicin 60 mg/m² and cyclophosphamide (Cytoxan, Neosar) 600 mg/m² as first-line treatment of
metastatic breast cancer. At the time of publication, more than 230 patients have been recruited.
References:
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