Introduction
In the United States each year, more than 180,000 women are diagnosed with breast cancer and more than 45,000 die of the disease each year.[1] In spite of major advances in adjuvant therapy, metastatic breast cancer remains a major clinical problem affecting large numbers of patients.
For many years, standard-dose combination chemotherapy has been the mainstay of therapy for metastatic disease that is hormone resistant, estrogen-receptor negative, or associated with life-threatening or visceral disease. The choice of initial chemotherapy has been combination cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan)/methotrexate/5-fluorouracil (5-FU) (CMF) or CMF with prednisone(Drug information on prednisone) (CMFP), with or without vincristine (Oncovin) followed by anthracycline, or doxorubicin(Drug information on doxorubicin) (Adriamycin)-containing combinations.[2-4] The choice of initial chemotherapy is often complicated by early relapse in patients who have received adjuvant chemotherapy.
CMF COMBINATION CHEMOTHERAPY
When first described by Cooper,[5] the CMF combination was reported to induce high response rates. Modern criteria and increasingly sophisticated imaging procedures for assessment of the extent of disease and response have shown that the CMF regimen, with or without vincristine and prednisolone(Drug information on prednisolone), produces objective responses in about 37% to 59% of patients (Table 1).[2,6-14] Perhaps more significant, median response duration ranges from 6 to 11 months, and the median survival from initiation of treatment ranges from 7 to 16 months.
CMF Combinations and Doxorubicin
Doxorubicin alone has been shown to be as active as CMF in randomized studies of patients with advanced breast cancer.[2,8,15,16] In these studies, single-agent doxorubicin produced shorter response durations than CMF, but there was no obvious difference in survival. Survival was difficult to interpret, however, because patients were often crossed over to the alternative regimen on progression.
Six randomized studies of cyclophosphamide/doxorubicin/5-FU (CAF) versus CMF in advanced breast cancer have been reviewed by Henderson.[17-23] Three of the six showed significantly higher response rates with the CAF combination, but only two of six showed a statistically significant survival advantage for the doxorubicin combination.
These studies have been interpreted as showing a slight advantage for doxorubicin combinations in treatment of metastatic breast cancer.[17] This interpretation is controversial, and any improvement in outcome with standard-dose doxorubicin combinations compared to CMF is likely to be marginal.
An Australian randomized study compared doxorubicin/cyclophospha mide (AC) with CMFP in 305 previously untreated patients with metastatic breast cancer.[12] The response, response duration, and survival were similar with either CMFP or AC given continuously until relapse. There also was no difference in the effect of either regimen on life-threatening or visceral disease. The doxorubicin combination was associated with significantly more nausea, vomiting, and alopecia than was the CMFP combination. A quality-of-life assessment by patients on this study revealed that the parameter measuring nausea and vomiting deteriorated for patients on AC, but not for those on CMFP.
This Australian trial provided a rationale for the use of CMFP as the control arm of a phase III randomized trial of CMFP versus paclitaxel(Drug information on paclitaxel) (Taxol).
PACLITAXEL IN BREAST CANCER
Paclitaxel is a novel cytotoxic agent that binds to the beta-tubulin monomer, inducing permanent microtubular polymerization.[24,25] The resulting loss of dynamic reorganization of microtubules during mitosis results in selective blockade of the G2/M phase of cell division. This action in vitro correlates with clinical activity of paclitaxel.[26]
Paclitaxel, given as a 24-hour infusion, has been found to be active in previously treated patients with advanced breast cancer.[27] In a single-institution study conducted at the M.D. Anderson Cancer Center, Holmes reported 6 of 11 previously treated patients responded to paclitaxel therapy with similar responses seen in 8 of 14 patients who had prior adjuvant chemotherapy only.[27] Of six patients who were resistant to doxorubicin, two achieved a partial remission in response to paclitaxel. Since this initial report there have been a number of studies and reviews confirming that paclitaxel is active in previously treated and anthracycline-resistant breast cancer.[28-32] The reported response rates have been quite variable, however, ranging from 20% to 62% with similar variability in response duration.
The schedule of paclitaxel infusion also has varied, with most of the earlier studies using 24-hour infusions. Other studies have since reported 1-hour and 3-hour infusion times.[33-35] A large, randomized European-Canadian study compared two doses of paclitaxel (135 mg/m² vs 175 mg/m²) and two infusion times (3-hour vs 24-hour) in patients with relapsed ovarian cancer. In these ovarian cancer patients, there were no differences related to the two infusion rates. The incidence of hypersensitivity reactions was low and also was not influenced by dose or schedule. However, this study clearly demonstrated that the 24-hour paclitaxel infusion is associated with a significantly greater reduction in neutrophils following each course compared to the 3-hour infusion.[33] This observation has been confirmed by a recent randomized study comparing 3-, 6-, and 96-hour infusions of paclitaxel.[36] Greco and Hainsworth[35] showed that 1-hour paclitaxel infusions were safe, with the dose-limiting toxicity remaining leukopenia, as expected.[35] Although numbers were small, approximately 35% of previously treated patients with breast cancer responded to the 1-hour paclitaxel regimen, at a dose of 135 mg/m². According to these data, there is no compelling evidence that longer infusion times are associated with in creased efficacy, at least in ovarian cancer. Those data and the convenience of the shorter administration schedule have provided a rationale for exploration of shorter infusion times for the treatment of breast cancer.
PACLITAXEL VS CMFP IN UNTREATED METASTATIC BREAST CANCER
We have reported the preliminary results of a phase III randomized trial of CMFP versus paclitaxel in previously untreated patients with metastatic breast cancer.[37] Patients eligible for this study had measurable or evaluable metastatic breast cancer and had had no prior chemotherapy, except for adjuvant chemotherapy, for at least 6 months prior to study entry. No prior radiotherapy was permitted for at least 4 weeks prior to study entry. Patients were required to have Eastern Cooperative Oncology Group performance status of 0 to 2, adequate bone marrow function, liver function, and renal function. Responses and toxicity were evaluated using the criteria of the World Health Organization (WHO),[38] and patients were required to give written informed consent prior to enrollment.
Eligible patients were randomized to either paclitaxel or CMFP. Paclitaxel 200 mg/m² was given as a 3-hour continuous intravenous (IV) infusion every 21 days for a total of 8 courses over 24 weeks. Standard premedication included dexamethasone(Drug information on dexamethasone) 20 mg orally (PO) 12 and 6 hours prior to therapy, and diphenhydramine(Drug information on diphenhydramine) 50 mg IV and cimetidine(Drug information on cimetidine) 300 mg IV 30 minutes prior to paclitaxel. Standard antiemetics including metoclopramide, prochlorperazine(Drug information on prochlorperazine), ondansetron, and dexamethasone were given if required.
CMFP chemotherapy was given as cyclophosphamide 100 mg/m² PO daily on days 1 to 14, methotrexate(Drug information on methotrexate) 40 mg/m² IV on days 1 and 8, 5-FU 600 mg/m² IV on days 1 and 8, and prednisone 40 mg/m² PO daily days 1 to 14. This schedule was repeated every 4 weeks for six courses, over 24 weeks. Antiemetics were given as for the paclitaxel treatment arm. Upon completion of 6 months of therapy, chemotherapy was stopped and patients were observed until relapse.
Appropriate clinical assessment and imaging techniques for tumor evaluation were carried out at baseline and at 12 and 24 weeks unless the patient progressed clinically before that time. The routine assessments included quality-of-life evaluations previously used and reported by this group of investigators.[12] Patients whose disease progressed were recommended for subsequent treatment with single-agent epirubicin(Drug information on epirubicin).
