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

June 1, 1997

A pilot phase II study examined the feasibility of 75 mg/m² of docetaxel (Taxotere) in combination with 50 mg/m²of doxorubicin and 500 mg/m² of cyclophosphamide (Cytoxan, Neosar) in the first-line treatment of metastatic breast cancer. This study was designed to evaluate the efficacy and toxicity of the docetaxel/doxorubicin/cyclophosphamide combination both alone and as induction before high-dose chemotherapy, supplemented by autologous peripheral blood stem-cell transplantation.

ABSTRACT: A pilot phase II study examined the feasibility of 75 mg/m² of docetaxel (Taxotere) in combination with 50 mg/m²of doxorubicin and 500 mg/m² of cyclophosphamide (Cytoxan, Neosar) in the first-line treatment of metastatic breast cancer. This study was designed to evaluate the efficacy and toxicity of the docetaxel/doxorubicin/cyclophosphamide combination both alone and as induction before high-dose chemotherapy, supplemented by autologous peripheral blood stem-cell transplantation. Patients were divided into three groups: one group received 8 courses of docetaxel/doxorubicin/cyclophosphamide; the second received 4 to 6 courses of the same combination with cell sampling, followed by high-dose chemotherapy with autologous peripheral blood stem-cell transplantation; and the third group's regimen was identical to that of the second, with additional granulocyte-colony stimulating factor (G-CSF, filgrastim [Neupogen]). Of 28 patients (149 courses) evaluable for toxicity and response, the overall response rate was 82%, with 5 (18%) complete responses and 18 (64%) partial responses. The most frequent hematologic toxicity was neutropenia; grade 4 neutropenia occurred in 86% of patients, with febrile neutropenia in 9 patients (18%). There was no incidence of infection, possibly because of the administration of oral ciprofloxacin (Cipro) from days 5 to 15 of each cycle. Nonhematologic adverse events were not severe; there was no significant cardiotoxicity. Future randomized trials of docetaxel/doxorubicin/cyclophosphamide as first-line adjuvant therapy of high-risk patients and as induction chemotherapy are in development. [ONCOLOGY 11(Suppl 6):25-27, 1997]

Introduction

To be useful in the clinical setting, the taxanes must be integratedinto multi-agent chemotherapy. The combination of paclitaxel (Taxol) anddoxorubicin has proven highly effective, but its utility is limited bythe incidence of cardiotoxicity.[1,2] Docetaxel (Taxotere) has also shownpromising results in combination with doxorubicin.[3] Phase II studiessuggest that with doses of 75 mg/m² of docetaxel and 50 mg/m²ofdoxorubicin, there is no clinically significant cardiotoxicity.[4]

These observations led to a feasibility study using docetaxel, doxorubicin,and cyclophosphamide (Cytoxan, Neosar) in combination. The efficacy andsafety of this combination alone and as induction before high-dose chemotherapy,supplemented by autologous peripheral blood stem-cell transplantation (APBSCT),were evaluated in a pilot phase II trial.

This study will serve as the basis for an imminent international programof randomized trials.

Objectives

The primary objective of this study was to determine the feasibilityof a docetaxel/doxorubicin/cyclophosphamide regimen in two subgroups ofpatients. The first group received eight courses of the regimen alone.The second group received 4 to 6 courses of the regimen in a nonrandomizedfashion as induction chemotherapy before high-dose mitoxantrone (Novantrone),cyclophosphamide, and vinorelbine (Navelbine), supplemented by autologousperipheral blood stem-cell transplantation. The toxicity profile of thecombination regimen and the role of prophylactic oral ciprofloxacin (Cipro)were evaluated.

The second objective was to assess the efficacy in terms of responserate and progression-free survival. The third objective was to evaluatethe capacity of the docetaxel/doxorubicin/cyclophosphamide regimen to primeperipheral stem cells before harvesting them for potential autologous peripheralblood stem-cell transplantation. The effect of the regimen alone and incombination with granulocyte colony-stimulating factor (G-CSF, filgrastim[Neupogen]) support was evaluated.

Patient Profiles

Female patients between the ages of 18 and 75 years with measurablemetastatic breast cancer were eligible for inclusion into the study. Priortreatment using adjuvant and/or neoadjuvant chemotherapy without anthracyclinesand hormonal therapy at the adjuvant and/or metastatic stage were permitted.Patients had to have normal cardiac function on multiple gated acquisitionscan, normal visceral status (as determined by liver status), and Karnofskyindex performance status over 60%.

Treatment Regimen

Group 1

In the first group, patients received 75 mg/m² of docetaxel, 50mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide as 1course every 3 weeks (Figure 1). Cyclophosphamidewas administered first, followed by doxorubicin, and then docetaxel asa 1-hour infusion beginning 1 hour after doxorubicin. All patients receivedsteroid premedication for 3 days before chemotherapy. Patients receiveda total of 8 courses of the regimen.

Group 2

In the second group, patients received 4 to 6 courses of docetaxel/doxorubicin/cyclophosphamideas induction chemotherapy, followed by a course of high-dose chemotherapyand autologous peripheral blood stem-cell transplantation.

Patients were administered 2 to 4 courses of the docetaxel/doxorubicin/cyclophosphamideregimen initially to obtain a major response and were then split into 2subgroups. Each subgroup received an additional 2 courses of the regimenwith cell sampling 3 times a week; ie, harvest of peripheral blood stemcells and determination of stem-cell kinetics (granulocyte-macrophage colony-formingunits [GM-CFU] and CD34+ cells). One subgroup received additional G-CSFafter high-dose chemotherapy, and the other subgroup did not (Figure1). High-dose chemotherapy consisted of 64 mg/m² of mitoxantrone,6 g/m² of cyclophosphamide, and 85 to 105 mg/m² of vinorelbine,administered over 4 days. The phase I program for this regimen increasedthe vinorelbine dosage from 45 to 95 mg/m², infused over 96 hours,and found a maximum tolerated dose of 85 mg/m².[5]

Results

Patient Characteristics

Over a 6-month period, 42 patients were enrolled. Their mean age was52 years (range, 43 to 70 years). Seven patients (25%) had received prioradjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil(5-FU). None had received anthracycline chemotherapy. The sites of metastaseswere mostly visceral: 18 patients (64%) had visceral metastases, 15 (54%)had bone metastases, and 11 patients (39%) had more than three metastaticsites. The majority of the patients were functioning well: 26 (92%) hada Karnofsky index over 80% before treatment.

Of the patients receiving docetaxeldoxorubicin/cyclophosphamide, 28were evaluable for toxicity and response. These patients had received attotal of 165 courses, 149 of which were evaluable, for an average of 5.3courses per patient. Some of the patients had not had the full regimenof courses, and the results presented here are preliminary.

Efficacy

The major response rate was 82%, with five (18%) complete responsesand 18 (64.0%) partial responses. Another five patients (18%) had stabledisease, and no patient had disease progression.

Toxicity

The most frequent hematologic toxicity was neutropenia. No anemia orthrombocytopenia was observed. Grades 1 and 2 neutropenia occurred in twopatients (7.1%), and grade 3 occurred in 26 patients (92.8%). In 24 patients(85.7%), neutropenia progressed to grade 4. Neutropenia occurred early,generally lasting less than 7 days, with a low incidence of fever. Ninepatients (32%) had febrile neutropenia, but none developed an infection.Oral ciprofloxacin (500 mg twice daily) was administered from days 5 to15 in 137 of the 149 evaluable courses. Table1 describes the cumulative incidence of neutropenia in the evaluablecourses.

Nonhematologic adverse events were not severe, with no grade 4 toxicityand only 9 courses with grade 3 toxicity, none clinically significant.The most common events were fatigue, pain, and vomiting (Table2). There were no significant problems with fluid retention at thisdosage of docetaxel.

Multiple-gated acquisition scans were performed every other course.In only 1 of the 28 patients (3.6%), left-ventricular ejection fractionfell more than 10%. There was no clinically significant cardiotoxicityand no cardiac failure.

Discussion

These results, although preliminary, demonstrate a lack of clinicallysignificant cardiotoxicity compared with that seen with the combinationof paclitaxel and an anthracycline.[1] The high response rate and low incidenceof toxicity justify additional trials of the docetaxel/doxorubicin/ cyclophosphamideregimen as adjuvant therapy. Historical comparison of this regimen with5-FU/doxorubicin/cyclophosphamide and 5 mg/kg of G-CSF shows that the formerprovides better priming.[5]

References:

1. Gianni L, Capri G, Tarenzi E, et al: Efficacy and cardiac effectsof 3-h paclitaxel (P) plus bolus doxorubicin (DOX) in women with untreatedmetastatic breast cancer (abstract). Proc Am Soc Clin Oncol 15:116, 1996.

2. Dombernowsky P, Gehl J, Boesgaard M, et al: Treatment of metastaticbreast cancer with paclitaxel and doxorubicin. Semin Oncol 22(6; suppl15):13-17, 1995.

3. Diéras V, Gruia M, Pouillart P, et al: A phase I study ofthe combination of docetaxel (D) and Adriamycin (A) in first line CT treatmentof metastatic breast cancer (MBC) (abstract). Eur J Cancer 31A(suppl 5):S194-195,1995.

4. Diéras V: Docetaxel in combination with doxorubicin. A phaseI dose-finding study (abstract). Proc Am Soc Clin Oncol 15:148, 1996.

5. Nabholtz J-M: Manuscript in preparation.