TAXOL remained active in patients who had developed resistance to platinum-containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum-containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 and 2 clinical studies.

The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (TABLES 10 and 12) and narrative form.

The results of this randomized study support the use of TAXOL at doses of 135 to 175 mg/m², administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.

Breast Carcinoma

Adjuvant Therapy

A Phase 3 Intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group [ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG]) randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with TAXOL or to no further chemotherapy following 4 courses of doxorubicin and cyclophosphamide (AC). This multicenter trial was conducted in women with histologically positive lymph nodes following either a mastectomy or segmental mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety of 3 different dose levels of doxorubicin (A) and to evaluate the effect of the addition of TAXOL administered following the completion of AC therapy. After stratification for the number of positive lymph nodes (1–3, 4–9, or 10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m² and doxorubicin at doses of either 60 mg/m² (on day 1), 75 mg/m² (in 2 divided doses on days 1 and 2), or 90 mg/m² (in 2 divided doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for 4 courses and either TAXOL 175 mg/m² as a 3-hour infusion every 3 weeks for 4 additional courses or no additional chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation after recovery from treatment-related toxicities.

At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall survival used multivariate Cox models, which included TAXOL administration, doxorubicin dose, number of positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the model for disease-free survival, patients receiving AC followed by TAXOL had a 22% reduction in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio [HR]=0.78, 95% CI, 0.67–0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI, 0.60–0.92, p=0.0065). For disease-free survival and overall survival, p-values were not adjusted for interim analyses. Kaplan- Meier curves are shown in FIGURES 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m² had no effect on either disease-free survival or overall survival.

FIGURE 3: DISEASE-FREE SURVIVAL: AC VERSUS AC+T

FIGURE 4: SURVIVAL: AC VERSUS AC+T

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