To be useful in the clinical setting, the taxanes must be integrated
into multi-agent chemotherapy. The combination of paclitaxel (Taxol) and
doxorubicin has proven highly effective, but its utility is limited by
the incidence of cardiotoxicity.[1,2] Docetaxel (Taxotere) has also shown
promising results in combination with doxorubicin. Phase II studies
suggest that with doses of 75 mg/m² of docetaxel and 50 mg/m²of
doxorubicin, there is no clinically significant cardiotoxicity.
These observations led to a feasibility study using docetaxel, doxorubicin,
and cyclophosphamide (Cytoxan, Neosar) in combination. The efficacy and
safety 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 program
of randomized trials.
The primary objective of this study was to determine the feasibility
of a docetaxel/doxorubicin/cyclophosphamide regimen in two subgroups of
patients. The first group received eight courses of the regimen alone.
The second group received 4 to 6 courses of the regimen in a nonrandomized
fashion as induction chemotherapy before high-dose mitoxantrone (Novantrone),
cyclophosphamide, and vinorelbine (Navelbine), supplemented by autologous
peripheral blood stem-cell transplantation. The toxicity profile of the
combination regimen and the role of prophylactic oral ciprofloxacin (Cipro)
The second objective was to assess the efficacy in terms of response
rate and progression-free survival. The third objective was to evaluate
the capacity of the docetaxel/doxorubicin/cyclophosphamide regimen to prime
peripheral stem cells before harvesting them for potential autologous peripheral
blood stem-cell transplantation. The effect of the regimen alone and in
combination with granulocyte colony-stimulating factor (G-CSF, filgrastim
[Neupogen]) support was evaluated.
Female patients between the ages of 18 and 75 years with measurable
metastatic breast cancer were eligible for inclusion into the study. Prior
treatment using adjuvant and/or neoadjuvant chemotherapy without anthracyclines
and hormonal therapy at the adjuvant and/or metastatic stage were permitted.
Patients had to have normal cardiac function on multiple gated acquisition
scan, normal visceral status (as determined by liver status), and Karnofsky
index performance status over 60%.
In the first group, patients received 75 mg/m² of docetaxel, 50
mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide as 1
course every 3 weeks (Figure 1). Cyclophosphamide
was administered first, followed by doxorubicin, and then docetaxel as
a 1-hour infusion beginning 1 hour after doxorubicin. All patients received
steroid premedication for 3 days before chemotherapy. Patients received
a total of 8 courses of the regimen.
In the second group, patients received 4 to 6 courses of docetaxel/doxorubicin/cyclophosphamide
as induction chemotherapy, followed by a course of high-dose chemotherapy
and autologous peripheral blood stem-cell transplantation.
Patients were administered 2 to 4 courses of the docetaxel/doxorubicin/cyclophosphamide
regimen initially to obtain a major response and were then split into 2
subgroups. Each subgroup received an additional 2 courses of the regimen
with cell sampling 3 times a week; ie, harvest of peripheral blood stem
cells and determination of stem-cell kinetics (granulocyte-macrophage colony-forming
units [GM-CFU] and CD34+ cells). One subgroup received additional G-CSF
after high-dose chemotherapy, and the other subgroup did not (Figure
1). 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 increased
the vinorelbine dosage from 45 to 95 mg/m², infused over 96 hours,
and found a maximum tolerated dose of 85 mg/m².
Over a 6-month period, 42 patients were enrolled. Their mean age was
52 years (range, 43 to 70 years). Seven patients (25%) had received prior
adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil
(5-FU). None had received anthracycline chemotherapy. The sites of metastases
were mostly visceral: 18 patients (64%) had visceral metastases, 15 (54%)
had bone metastases, and 11 patients (39%) had more than three metastatic
sites. The majority of the patients were functioning well: 26 (92%) had
a Karnofsky index over 80% before treatment.
Of the patients receiving docetaxeldoxorubicin/cyclophosphamide, 28
were evaluable for toxicity and response. These patients had received at
total of 165 courses, 149 of which were evaluable, for an average of 5.3
courses per patient. Some of the patients had not had the full regimen
of courses, and the results presented here are preliminary.
The major response rate was 82%, with five (18%) complete responses
and 18 (64.0%) partial responses. Another five patients (18%) had stable
disease, and no patient had disease progression.
The most frequent hematologic toxicity was neutropenia. No anemia or
thrombocytopenia was observed. Grades 1 and 2 neutropenia occurred in two
patients (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. Nine
patients (32%) had febrile neutropenia, but none developed an infection.
Oral ciprofloxacin (500 mg twice daily) was administered from days 5 to
15 in 137 of the 149 evaluable courses. Table
1 describes the cumulative incidence of neutropenia in the evaluable
Nonhematologic adverse events were not severe, with no grade 4 toxicity
and only 9 courses with grade 3 toxicity, none clinically significant.
The most common events were fatigue, pain, and vomiting (Table
2). There were no significant problems with fluid retention at this
dosage of docetaxel.
Multiple-gated acquisition scans were performed every other course.
In only 1 of the 28 patients (3.6%), left-ventricular ejection fraction
fell more than 10%. There was no clinically significant cardiotoxicity
and no cardiac failure.
These results, although preliminary, demonstrate a lack of clinically
significant cardiotoxicity compared with that seen with the combination
of paclitaxel and an anthracycline. The high response rate and low incidence
of toxicity justify additional trials of the docetaxel/doxorubicin/ cyclophosphamide
regimen as adjuvant therapy. Historical comparison of this regimen with
5-FU/doxorubicin/cyclophosphamide and 5 mg/kg of G-CSF shows that the former
provides better priming.
1. Gianni L, Capri G, Tarenzi E, et al: Efficacy and cardiac effects
of 3-h paclitaxel (P) plus bolus doxorubicin (DOX) in women with untreated
metastatic breast cancer (abstract). Proc Am Soc Clin Oncol 15:116, 1996.
2. Dombernowsky P, Gehl J, Boesgaard M, et al: Treatment of metastatic
breast cancer with paclitaxel and doxorubicin. Semin Oncol 22(6; suppl
3. Diéras V, Gruia M, Pouillart P, et al: A phase I study of
the combination of docetaxel (D) and Adriamycin (A) in first line CT treatment
of metastatic breast cancer (MBC) (abstract). Eur J Cancer 31A(suppl 5):S194-195,
4. Diéras V: Docetaxel in combination with doxorubicin. A phase
I dose-finding study (abstract). Proc Am Soc Clin Oncol 15:148, 1996.
5. Nabholtz J-M: Manuscript in preparation.