Adjuvant Docetaxel Bests FAC in Breast Ca

SAN ANTONIO—Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) improved overall survival by 30% and disease-free survival by 28% at 5 years, compared with the standard combination of flu-orouracil, doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for women with node-positive, early-stage breast cancer, John R. Mackey, MD, reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 43).

Dr. Mackey, of the Cross Cancer Institute, Edmonton, Alberta, Canada, reported the second planned interim analysis of the Breast Cancer International Research Group (BCIRG) 001 study with 55 months of follow-up.

This Aventis-sponsored study is a head-to-head comparison of docetaxel-based chemotherapy and fluorouracil-based chemotherapy in 1,491 pre- and postmenopausal women with stage T1-3, N1, M0 breast cancer. Eligibility criteria included no prior systemic therapy or radiotherapy for breast cancer, age of 70 or younger, and definitive surgical treatment of mastectomy or breast-conserving surgery that included axillary lymph node dissection.

The primary study endpoint is disease-free survival. Secondary endpoints are overall survival, toxicity, quality of life, and evaluation of pathologic and molecular markers for predicting efficacy. Enrollment began in June 1997 and was completed in June 1999, including patients from 111 sites in 20 countries.

After surgery, patients were randomized to TAC (n = 745) or FAC (n = 746). Planned subgroup analyses include hormone-receptor status and nodal involvement (one to three vs four or more positive nodes). Most patients had at least 2-cm tumors, two thirds had one to three positive nodes, and 75% were hormone-receptor positive.

Tumor samples were collected from 95% of patients for analysis of hormone- receptor status, HER-2 amplification, and other characteristics. Quality of life analyses are being done, and Dr. Mackey said they will be presented this year.

The first planned interim analysis of this study, with a median follow-up of 33 months, was presented at the American Society of Clinical Oncology 2002 annual meeting (abstract 141) and showed significant improvement in disease-free survival in favor of TAC. The data reported by Dr. Mackey confirmed and extended these findings. This second interim analysis was done after 400 disease-free survival events. The final analysis will be after 590 events.

For disease-free survival, Dr. Mackey reported 172 events on TAC and 227 on FAC. Five-year disease-free survival using intent-to-treat analysis was 75% on TAC vs 68% on FAC (HR 0.72, P = .0010). For overall survival, there were 91 events on TAC and 130 on FAC. Overall survival at 5 years was 87% on TAC and 81% on FAC (HR 0.70, P = .008).

The TAC advantage was seen in both HER-2-positive and HER-2-negative patients. The TAC/FAC disease-free survival hazard ratio was 0.61 (P = .0118) in HER-2-positive patients, and 0.76 (P = .0380) in HER-2-negative patients.

Disease-free survival was also significantly better for TAC vs FAC for patients with one to three positive nodes (HR 0.61, P = .0009). Disease-free survival with TAC was better in patients with four or more positive nodes but not significantly so (HR 0.83, P = .17). There was no interaction of nodal status per se with disease-free survival, Dr. Mackey said.

The benefits of TAC were significant in both hormone-receptor-positive and hormone-receptor-negative patients.

Febrile neutropenia was 24.7% with TAC vs 2.5% with FAC (P < .005), but this did not result in more moderate to severe infections in patients who received TAC. Grade 3 or 4 neutropenia was 65.5% vs 49.3% (P < .05). The study protocol did not include prophylactic G-CSF (Neupogen). There were no toxic deaths or long-lasting toxicities on either arm.

Dr. Mackey said that the total number of second primary cancers was lower with TAC than with FAC and that there has been no sign of leukemogenesis, although this is being watched closely.

"TAC produced a significant increase in disease-free survival with a 28% reduction in risk of relapse and an overall survival advantage with a 30% reduction in mortality. The disease-free survival advantage was irrespective of nodal status, estrogen-receptor status, or HER-2 status," Dr. Mackey said. "This establishes docetaxel as a source of major clinical benefit in the adjuvant treatment of early, node-positive breast cancer. We are confident that this docetaxel-based treatment can cure more women than one of the standard chemotherapy regimens."

A statement from Aventis said that the company "plans to use the phase III study data to support submissions for US and European Union approval in early 2004 for the use of Taxotere in treating early-stage operable breast cancer with involved axillary lymph nodes."