Paclitaxel and Epirubicin as First-Line Therapy for Patients With Metastatic Breast Cancer

April 1, 1997

Paclitaxel (Taxol) has aroused considerable interest for its high single-agent activity in breast cancer and novel mechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin (Adriamycin), also has high activity in

ABSTRACT: Paclitaxel (Taxol) has aroused considerableinterest for its high single-agent activity in breast cancer and novelmechanism of action. Epirubicin (Farmorubicin), the 4'epimer of doxorubicin(Adriamycin), also has high activity in breast cancer, with the advantageof a lower rate of toxic side effects—especially cardiac effects—comparedwith its parent compound. The combination of paclitaxel and doxorubicinhas yielded response rates between 63% and 94% in phase I/II studies, butauthors reported severe cardiac toxic events. The goal for the currentstudy was to evaluate the combination of paclitaxel and epirubicin, focusingmainly on cardiac toxicity. Of a total of 85 patients entered, 68 patientswith metastatic breast cancer were evaluable. Nearly 20% had primary metastaticbreast cancer with large tumors. Half had received adjuvant chemotherapy.Study medication in Group A consisted of 60 mg/m² epirubicingiven over 1 hour, followed by paclitaxel 175 mg/m² administered asa 3-hour IV infusion. In Group B, 90 mg/m²epirubicin was combinedwith 175 mg/m² paclitaxel, delivered as for Group A. The main toxicityin both groups was neutropenia. In Group A, the paclitaxel dose could beescalated to 200 mg/m² in 15 patients and to 225 mg/m² in 7 patients;dose reduction due to severe neutropenia was necessary in 11 patients.No cardiac adverse events were reported in Group A. In Group B, only onepatient could be escalated to 200 mg/m², but three patients requireda dose reduction. In this group, one patient had a decrease of left ventricularejection fraction of more than 10% without any clinical signs. Of 43 patients in Group A and 25 in Group B, the response rate was67% in Group A and 68% in Group B. The duration of response was 8.2 monthsin both groups. The combination of paclitaxel 175 mg/m² and epirubicin60 mg/m² or 90 mg/m² can be safely administered to patients withmetastatic breast cancer. The response data were encouraging, and furtherevaluation is warranted. [ONCOLOGY 11(Suppl):34-37, 1997]

Introduction

Paclitaxel (Taxol) is a taxane known for its high activity in breastand ovarian cancer.[1] Its effectiveness in breast cancer was originallyobserved by Holmes et al[2] and Reichman et al[3] whose impressive studyresults indicated that paclitaxel has a high degree of activity comparedwith other standard chemotherapies for metastatic breast cancer, as wellas significant activity in patients who had received multiple prior chemotherapies.In addition, these investigators' studies showed that clinical resistanceto doxorubicin (Adriamycin) does not predict resistance to paclitaxel.

These results motivated evaluation of a combination of paclitaxel andanthracyclines, which are the other most active drugs available for treatmentof metastatic breast cancer. Holmes et al[4] performed a phase I trialusing paclitaxel given by 24-hour intravenous infusion, followed by doxorubicinby 48-hour continuous infusion. The dose-limiting toxicity of that trialwas mucositis, which occurred with relatively low doses of both substances.Sledge et al[5] repored a phase I study using the same regimen, but thereverse sequence: the doxorubicin infusion was followed after 4 hours bythe 24-hour paclitaxel infusion. The rate of severe mucositis developingwith this schedule was very low. The maximum tolerated doses identifiedwere doxorubicin 50 mg/m² and paclitaxel 150 mg/m². In otherstudies, Dombernowsky et al[6] and Gianni et al[7] reported high responserates (94%) in patients with previously untreated metastatic breast cancertreated with paclitaxel combined with doxorubicin. In those studies, paclitaxelwas given as a 3-hour infusion. The main toxicities encountered were neutropeniaand febrile neutropenia, and both studies described severe cardiac toxicitiesin 15% to 25% of patients.

Epirubicin (Farmorubicin), the 4'epimer of doxorubicin, is equieffectivebut less toxic than its parent compound, particularly with respect to cardiactoxicity.[8] Medline search recalled eight trials in which patients withmetastatic breast cancer were comparatively treated with doxorubicin vsepirubicin.[9-17] This phase II study was therefore designed to evaluatethe safety and feasibility of the combination paclitaxel/ epirubicin, withparticular emphasis on cardiac side effects.

Patients and Methods

Only patients with histologically proven breast cancer were recruitedfor this trial. Eligible patients were permitted to have undergone oneadjuvant chemotherapy or hormone therapy course or one palliative hormonetherapy course. The adjuvant therapy could have included anthracyclinesdosed to 300 mg/m². Other eligibility requirements included measurablemetastasis and normal hematologic, renal, and hepatic function. Patientsalso were required to be between 18 and 70 years of age and to have a lifeexpectancy of more than 12 weeks.

The first 57 patients entered (Group A) were treated with epirubicin60 mg/m² intravenously, given as a 1-hour infusion, followed by paclitaxel175 mg/m² intravenously over 3 hours. The next 28 patients entered(Group B) received epirubicin 90 mg/m² intravenously over 1 hour,followed by the same starting dose and regimen of paclitaxel as was given to Group A. All patients were premedicated with dexamethasone 20mg given orally 12 and 6 hours before paclitaxel, and clemastine (Tavist)2 mg intravenously and ranitidine (Zantac) 50 mg intravenously 30 minutesprior to paclitaxel. Patients with congestive heart failure were not eligiblefor the study.

Study Design

Cardiac monitoring involved evaluation of left ventricular ejectionfraction after every second cycle. Paclitaxel dose escalation was permittedin 25 mg/m² steps to a maximum of 225 mg/m², assuming a neutrophilnadir of 1or more x 109/L, a thrombocyte nadir of 100 or morex 109/L, and peripheral neuropathy lower than grade 2, withoutgranulocyte colony-stimulating factor support. In case of higher grades,the paclitaxel dose could be reduced to 100 mg/m², again in 25 mg/m²steps.

Results

Of 57 and 28 patients enrolled in Groups A and B, respectively, 43 patientsin Group A and 25 patients in Group B were evaluable for response and toxicity.The median age of patients entered in study groups A and B was 51 and 55years, respectively, and the median Eastern Cooperative Oncology Groupperformance index for all patients was 0. The majority of entered patientswere postmenopausal (Group A, 62%; Group B, 76%), and most had poorly differentiatedtumors (Group A, 63%; Group B, 74%). Adjuvant chemotherapy had been administeredto 51% of patients in Group A and 36% of patients in Group B.

Nearly 20% of patients had primary metastatic breast cancer with a largetumor at the primary site. The localization of metastases is summarizedin Table 1. More than 80% of the patientshad two or more lesions (Table 2).

Toxicity

The main toxicity encountered was neutropenia. No febrile episodesoccurred in Group A, but there were two episodes in Group B. World HealthOrganization grade 3 or 4 neutropenia was reported in 80.9% of the coursesoverall. Thrombocytopenia and anemia were observed in less than 1% of thecourses (Table 3). Alopecia was observedin all patients treated with more than two cycles. No peripheral neuropathyWorld Health Organization grade greater than 2 was reported and myalgiaWorld Health Organization grade 3 was noted in only 1% of cycles. Severenausea and emesis were observed in 2% of the cycles (Table4). No incidence of mucositis was described.

To date, no cardiac toxicity has been seen. The left ventricular ejectionfraction was checked by echocardiography or cardiac scintigraphy in GroupA, but one episode without clinical signs occurred in Group B.

Dose Escalation

In 15 patients from Group A we were able to escalate the paclitaxeldose to 200 mg/m² and in seven of these patients further escalationto 225 mg/m² was possible. In Group B, only one patient could be escalatedto 200 mg/m² and no patient was escalated to 225 mg/m². In GroupA, severe neutropenia necessitated reduction of the paclitaxel dose to135 mg/m² in 11 patients, and further to 110 mg/m² in four ofthem. In Group B, three patients required dose reduction to 135 mg/m²

Response

Response rate was not a primary concern of this study, but it is oneof the checkpoints of oncology treatment. In this poor-prognosis studygroup we achieved an overall response rate of 68% in Group A and 71% inGroup B (Table 5). In 50% of patientswho attained a remission, response occurred after the second cycle of treatment,while 25% of the patients had their best response after the fourth cycle,and 25% after the sixth cycle.

The median follow-up was 14.1 months in Group A and 8.2 months in GroupB. The median progression-free interval was 8.2 months in both groups witha range of 5.3 to 11.3 months in Group A and 7.90 to 8.5 months in GroupB. For patients in Group A, the median progression-free interval was 12.5months (95% confidence interval [CI], 9.7 to 15.3) for those attaininga complete response and 8.1 months (95% CI 6.7 to 10.3) for those witha partial response. In Group B, the median progression-free interval forthe patients with a complete response has not been reached, but patientswith a partial response had an interval of 8.2 months (95% CI, 7.8 to 8.5).The median overall survival for those in Group A was 15.9 months (95% CI,12.8 to 19), whereas in Group B the median survival has not been reached.

Discussion

The combination of paclitaxel 175 mg/m²and epirubicin60 or 90 mg/m² showed remarkable efficacy against metastatic breastcancer with an overall response of 68% in the group treated with epirubicin60 mg/m² and 71% in those treated with epirubicin 90 mg/m². Thetreatment was generally well tolerated, although the higher epirubicindose induced more severe neutro penia and one case of cardiotoxicity. Thenonhematologic toxicities were mild and no cases of severe mucositis orperipheral neuropathy were reported. The higher epirubicin dose did notprolong progression-free survival. The observed remission rates were lowerthan those reported in the study from Gianni et al,[7] but the progression-freeinterval was in the same range.

In October 1996, the German AGO Study Group initiated a phase III trialcomparing the combination of paclitaxel 175 mg/m² and epirubicin 60mg/m² with the standard combination of epirubicin 60 mg/m² andcyclophosphamide (Cytoxan) 600 mg/m² as first-line treatment of metastaticbreast cancer.

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